TNF-alpha production inhibitors

ABSTRACT

A purpose of the present invention is to provide TNF-α production inhibitors being useful as therapeutic agents for autoimmune diseases such as rheumatoid arthritis. Novel compounds having the structure represented by the general formula [1] or salts thereof according to the present invention have excellent TNF-α production inhibitory activities, 
     
       
         
         
             
             
         
       
     
     wherein A is —(NR 4 )—, —(CR 5 R 6 )— or —O—, B is alkylene or alkenylene, R 1 , R 2 , R 4 , R 5  and R 6  are hydrogen, alkyl, alkenyl, adamantyl or the like, R 3  is aryl or an unsaturated heterocycle, and X is oxygen or sulfer respectively.

This application is a Divisional Application of application Ser. No.11/472,603, filed Jun. 22, 2006 which is a Divisional application ofSer. No. 10/168,777, filed Jun. 21, 2002 (U.S. Pat. No. 7,098,226) whichis the United States national phase application of InternationalApplication PCT/JP01/04586, filed May 31, 2001 which is herebyincorporated in its entirety by this reference.

TECHNICAL FIELD

The present invention relates to TNF-α production inhibitors beinguseful as therapeutic agents for autoimmune diseases such as rheumatoidarthritis.

BACKGROUND ART

TNF-α (Tumor necrosis factor-α) is recognized as a cytokine which widelyparticipates in biophylaxis-immune mechanism through inflammation. It isknown that prolonged and excessive production of TNF-α is a factor whichbrings about causes of tissue damage and various diseases. Examples ofpathology in which TNF-α participates are many pathology such asarthrorheumatism, systemic lupus erythematosus (SLE), cachexia, acuteinfectious disease, allergy, pyrexia, anemia and diabetes (Yamazaki,Clinical Immunology,. 27, 1270, 1995). It is also reported that TNF-αplays an important role in pathogenesis of rheumatoid arthritis andCrohn's disease, which are autoimmune diseases (Andreas Eigler et al.,Immunology Today, 18, 487, 1997).

From these reports, compounds which inhibit or suppress TNF-α productionare expected to be effective for treatment of the above-mentioneddiseases, and various studies have been done (the above-mentionedliteratures: Yamazaki, Clinical Immunology, 27, 1270, 1995, AndreasEigler et al., Immunology Today, 18, 487, 1997). Recently, it was alsoreported that metalloprotease, which is a proteolytic enzyme,participates in secretion of TNF-α and metalloprotease inhibitors haveimportant effects on the inhibition of TNF-α production and the like(Published Japanese Translation of PCT No. 508115/1997). JapaneseLaid-open Patent Publication Nos. 44533/2000 and 119249/2000 disclosecompounds having inhibitory effects of TNF-α production. All of thesecompounds are urea derivatives having a sulfur atom in side chains.

It is meaningful to search compounds having inhibitory activities ofTNF-α production and being useful as therapeutic agents for theautoimmune diseases such as rheumatoid arthritis, allergy and diabetes.

DISCLOSURE OF THE INVENTION

The present inventors prepared compounds having various chemicalstructures and carried out pharmacological tests. As a result, thepresent inventors found that novel compounds having structurerepresented by the following general formula [1] exhibit excellentinhibitory activities of TNF-α production to attain the presentinvention.

The present invention relates to compounds represented by the followinggeneral formula [1] and salts thereof (hereinafter referred to as “thepresent compound” as far as there is no proviso), and pharmaceuticalcompositions comprising it as an active ingredient,

wherein “A” is —(NR⁴)—, —(CR⁵R⁶)— or —O—;

“B” is alkylene or alkenylene which can contain —O—, —S—, —(NR⁷)—, —CO—,—N═ or a group represented by the following formula in its chain,

wherein the alkylene and alkenylene can be substituted by hydroxy,alkoxy, cycloalkyl, aryl, siloxy or a saturated or unsaturatedheterocycle and “B” can form a saturated heterocycle with “A”;

R¹, R², R⁴, R⁵ and R⁶, being the same or different, are hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, hydroxy, acyl or amino,wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl can besubstituted by halogen, hydroxy, amino, cycloalkyl, adamantyl, aryl,carboxy, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, cyano or asaturated or unsaturated heterocycle;

R¹ and R², R² and R⁴, R² and R⁵, and R² and R⁶ each can form a saturatedor unsaturated heterocycle;

R³ is aryl or an unsaturated heterocycle;

R⁷ is hydrogen or alkyl;

“X” is O or S;

“n” is an integer of 1 to 5; and

Each hydrogen of the above-mentioned amino, hydroxy and aminocarbonylcan be substituted by alkyl, cycloalkyl, adamantyl, adamantylalkyl,aryl, arylalkyl, acyl, alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl,cycloalkyloxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl, arylsulfonyl,halogenoalkyloxycarbonyl, imidazolylcarbonyl, pyridylcarbonyl, asaturated or unsaturated heterocycle, or alkyl substituted by asaturated or unsaturated heterocycle. The same definitions are appliedhereinafter.

The present compounds represented by the above general formula [1] areappropriate to constitute pharmaceutical compositions and are activeingredients of TNF-α production inhibitors being useful as therapeuticagents for autoimmune diseases such as rheumatoid arthritis, allergy anddiabetes.

Each group defined in the general formula [1] is described in detail.

The alkylene is straight-chain or branched alkylene having one to 12carbon atoms such as methylene, ethylene, trimethylene, propylene,tetramethylene, pentamethylene, hexamethylene, octamethylene,decamethylene, dodecamethylene, methylmethylene, ethylethylene,dimethylethylene, propylethylene, isopropylethylene ormethyltrimethylene.

The alkenylene is straight-chain or branched alkenylene having one ormore double bond and two to 12 carbon atoms such as vinylene,propenylene, butenylene, pentenylene, hexenylene, octenylene,butanediylidene or methylpropenylene.

The alkyl is straight-chain or branched alkyl having one to 12 carbonatoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl,dodecyl, isopropyl, isobutyl, isopentyl, isohexyl, isooctyl, t-butyl or3,3-dimethylbutyl.

The alkoxy is straight-chain or branched alkoxy having one to 12 carbonatoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, octyloxy,decyloxy, dodecyloxy, isopropoxy or t-butoxy.

The alkenyl is straight-chain or branched alkenyl having two to 12carbon atoms such as vinyl, allyl, 3-butenyl, 5-hexenyl or isopropenyl.

The alkynyl is straight-chain or branched alkynyl having two to 12carbon atoms such as ethynyl, propynyl or butynyl.

The cycloalkyl is cycloalkyl having three to 20 carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl or cyclododecyl.

The cycloalkenyl is cycloalkenyl having 5 to 20 carbon atoms such ascyclopentenyl, cyclohexenyl or cycloheptenyl.

The aryl is an aromatic hydrocarbon ring such as phenyl or naphtyl, andthe ring can have one or more substituent. Examples of the substituentare alkyl, cycloalkyl, carboxy, amino, hydroxy, aminoalkyl,hydroxyalkyl, nitro, cyano, halogen, alkyloxy and the like.

The siloxy is an organic group containing silicon such astrialkylsilyloxy, dialkyl(aryl)silyloxy, alkyl(diaryl)oxy ortriarylsilyloxy.

The halogen is fluorine, chlorine, bromine or iodine.

The heterocycle is, for example, a saturated or unsaturated five totwenty-membered monocyclic or bicyclic heterocycle containing one tofour nitrogen, oxygen and/or sulfur. The heterocycle can have one ormore substituent. Examples of the substituent are alkyl, cycloalkyl,carboxy, amino, hydroxy, aminoalkyl, hydroxyalkyl, nitro, cyano,halogen, alkyloxy, aryl, arylalkyl, a saturated or unsaturatedheterocycle and the like. When the above-mentioned heterocycle hasnitrogen or sulfur in its ring, the atom can be oxidized to be in theform of N-oxide, S-oxide or the like.

Specific examples of the saturated heterocycle are monocyclicheterocycles such as pyrrolidine, piperidine, homopiperidine andpiperazine, which have nitrogen in their ring, morpholine, which hasnitrogen and oxygen in its ring, and thiomorpholine, which has nitrogenand sulfur in its ring. These can condense with a benzene ring and thelike to form bicyclic heterocycles such as tetrahydroquinoline andtetrahydroisoquinoline.

Specific examples of the unsaturated heterocycle are monocyclicheterocycles such as pyrrole, pyridine, pyrazole, imidazole, pyrazine,pyridazine and pyrimidine, and bicyclic heterocycles such as indole,quinoline, isoquinoline, benzimidazole, naphthyridine, pyrrolopyridineand imidazopyridine, which have nitrogen in their ring, monocyclicheterocycles such as furan, and bicyclic heterocycles such asbenzofuran, which have oxygen in their ring, monocyclic heterocyclessuch as thiophene, and bicyclic heterocycles such as benzothiophene,which have sulfur in their ring, monocyclic heterocycles such asoxazole, isoxazole, thiazole and isothiazole, and bicyclic heterocyclessuch as benzoxazole, benzothiazole, thienopyridine, oxazolopyridine,thiazolopyridine and furopyridine, which have nitrogen and oxygen orsulfur in their ring, and the like. Further, the above-mentionedunsaturated heterocycles can contain saturated bonds partially.

Salts in the present invention refer to any pharmaceutically acceptablesalts and are exemplified by salts with an inorganic acid such ashydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, saltswith an organic acid such as acetic acid, fumaric acid, maleic acid,succinic acid or tartaric acid, salts with an alkali metal or analkaline-earth metal such as sodium, potassium or calcium, and the like.Quaternary ammonium salts of the present compounds are also included inthe salts in the present invention. Further when there are geometricalisomers or optical isomers in the present compounds, these isomers arealso included in the scope of the present invention. The presentcompounds can be in the form of hydrates and solvates.

Preferred examples in the present invention are the following compounds(1) to (3).

-   (1) Compounds or salts thereof wherein each group defined by the    general formula [1] is selected from the following 1) to 4) or the    groups are defined by combinations of two or more of 1) to 4).

1) R³: a pyridine ring.

2) At least one of R¹, R², R⁴, R⁵ and R⁶: adamantylalkyl,adamantyloxyalkyl, adamantylaminoalkyl or adamantylaminocarbonylalkyl.

3) At least one of R¹ and R²: adamantylalkyl, adamantyloxyalkyl,adamantylaminoalkyl or adamantylaminocarbonylalkyl.

4) At least one of R¹ and R²: adamantylalkyl.

-   (2) Compounds or salts thereof wherein the respective groups defined    by the general formula [1] are the following groups,

A: —(NR⁴)—, —(CR⁵R⁶)— or —O—,

B: alkylene or alkenylene which can contain —O—, —S—, —(NR⁷)—, —CO—, —N═or a group represented by the following formula in its chain,

wherein the alkylene can be substituted by hydroxy, alkoxy, aryl, siloxyor a saturated or unsaturated heterocycle and “B” can form a saturatedheterocycle with “A”,

R¹: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, hydroxyor amino, wherein the alkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl can be substituted by halogen, hydroxy, amino, cycloalkyl,aryl, carboxy, alkoxycarbonyl, alkylaminocarbonyl, adamantyl,aryloxycarbonyl, cyano or saturated or unsaturated heterocycle, and eachhydrogen of the amino hydroxy and aminocarbonyl in R¹ can be substitutedby alkyl, cycloalkyl, aryl, arylalkyl, acyl, alkoxycarbonyl,cycloalkyloxycarbonyl, arylalkoxycarbonyl, halogenoalkyloxycarbonyl,imidazolylcarbonyl, an unsaturated heterocycle, or alkyl substituted byan unsaturated heterocycle,

R²: adamantylalkyl, adamantyloxyalkyl, adamantylaminoalkyl oradamantylaminocarbonylalkyl,

R³: an unsaturated heterocycle,

R⁴: hydrogen, alkyl, adamantylalkyl, carboxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, amino, alkylamino, acylamino oralkoxycarbonylamino,

R⁵ and R⁶: being the same or different, hydrogen, alkyl, amino oralkoxycarbonylamino,

R⁷: hydrogen or alkyl,

X: O or S,

n: an integer of 1 to 5.

Compounds or salts thereof wherein R² is adamantylalkyl and R³ is apyridine ring are more preferable among them.

Further, compounds or salts thereof wherein the respective groupsdefined by the general formula [1] are the following groups areparticularly preferable.

A: —(NR⁴)—, —(CR⁵R⁶)— or —O—,

B: alkylene or alkenylene which can contain —S— or a group representedby the following formula in its chain,

R¹: alkyl or alkenyl, wherein the alkyl can be substituted by halogen oramino, and further the amino can be substituted by alkyl, acyl,arylalkyloxycarbonyl, cycloalkyloxycarbonyl or alkoxycarbonyl,

R²: adamantylalkyl,

R³: a pyridine ring,

R⁴: hydrogen,

R⁵ and R⁶: hydrogen,

X: O,

n: an integer of 1 to 5.

-   (3) Compounds or salts thereof wherein the respective groups defined    by the general formula [1] are the following groups,

A: —(NR⁴)—, (CR⁵R⁶)— or —O—,

B: alkylene or alkenylene which can contain —O—, —S—, —(NR⁷)—, —N═ or agroup represented by the following formula in its chain,

wherein the alkylene can be substituted by hydroxy, alkoxy, aryl or asaturated or unsaturated heterocycle and “B” can form a saturatedheterocycle with “A”,

R¹: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, hydroxyor amino, wherein the alkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl can be substituted by halogen, hydroxy, amino, cycloalkyl,aryl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, cyano ora saturated or unsaturated heterocycle, and each hydrogen of the amino,hydroxy and aminocarbonyl of R¹ can be substituted by alkyl, cycloalkyl,aryl, arylalkyl, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl,arylalkoxycarbonyl, an unsaturated heterocycle, or alkyl substituted byan unsaturated heterocycle,

R²: alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or arylalkyl,

R³: a pyridine ring,

R⁴: hydrogen, alkyl, adamantylalkyl, carboxyalkyl, alkoxycarbonylalkyl,amino, alkylamino, acylamino or alkoxycarbonylamino,

R⁵ and R⁶: being the same or different, hydrogen or alkyl,

R⁷: hydrogen or alkyl,

X: O or S,

n: an integer of 1 to 5.

Compounds or salts thereof wherein the respective groups defined by thegeneral formula [1] are the following groups are more preferable amongthem.

A: —(NR⁴)— or —(CR⁵R⁶)—,

B: alkylene or alkenylene,

R¹: alkyl or alkenyl, wherein the alkyl can be substituted by halogen,amino, cycloalkyl, aryl, imidazolyl or a pyridine ring, and further theamino can be substituted by alkyl, acyl, alkoxycarbonyl,cycloalkyloxycarbonyl or arylalkoxycarbonyl,

R²: alkyl, alkenyl or arylalkyl,

R³: a pyridine ring,

R⁴: hydrogen,

R⁵ and R⁶: hydrogen,

X: O.

Further, compounds or salts thereof wherein R¹ is alkyl having three ormore carbon atoms and R² is alkyl or arylalkyl are particularlypreferable among them.

Compounds or salts thereof wherein the respective groups defined by thegeneral formula [1] are the following groups are more preferable.

A: —(NR⁴)— or —(CR⁵R⁶)—,

B: alkylene or alkenylene,

R¹: alkyl, alkenyl or cycloalkyl, wherein the alkyl can be substitutedby halogen, hydroxy, amino, cycloalkyl, aryl, carboxy, alkoxycarbonyl,aryloxycarbonyl, aminocarbonyl, a pyridine ring or a thiophene ring, andfurther each hydrogen of the amino, hydroxy and aminocarbonyl in R¹ canbe substituted by alkyl, aryl, arylalkyl, acyl, alkoxycarbonyl,cycloalkyloxycarbonyl or arylalkoxycarbonyl,

R²: cycloalkyl or cycloalkylalkyl,

R³: a pyridine ring,

R⁴: hydrogen,

R⁵ and R⁶: hydrogen,

X: O.

The most preferred specific examples of the present compounds are thefollowing compounds and salts thereof.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea

1-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]-1-(3,3,3-trifluoropropyl)urea

1-[2-(1-Adamantyl)ethyl]-1-(2-butenyl)-3-[3-(4-pyridyl)propyl]urea

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea

1-[3-(1-Adamantyl)propyl]-1-propyl-3-[3-(4-pyridyl)propyl]urea

(Z)-1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea

(−)-1-[2-(1-Adamantyl)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea

1-[2-(1-Adamantyl)ethyl]-3-[1-methyl-3-(4-pyridyl)propyl]-1-pentylurea

(+)-1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]urea

5-(4-Pyridyl)valeric acid N-[2-(1-adamantyl)ethyl]-N-pentylamide

3-(4-Pyridylmethylthio)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide

2-[2-(4-Pyridyl)ethylthio]acetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide

6-(4-Pyridyl)caproic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide

cis-1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(4-pyridyl)cyclopropylmethyl]urea

1-[2-(1-Adamantyl)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]urea

(E)-1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea

(+)-1-[2-(1-Adamantyl)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea

1,1-Dibutyl-3-[3-(4-pyridyl)propyl]urea

3-[2-Methyl-3-(4-pyridyl)propyl]-1-pentyl-1-phenethylurea

5-(4-Pyridyl)valeric acid N-pentyl-N-phenethylamide

1-(2-Cyclohexylethyl)-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea

The present compounds can be prepared, for example, according to thefollowing reaction routes 1 to 3. The present compounds can be preparedby not only these reaction routes but also various reaction routes.Detailed synthetic methods will be described in the later Examples.

The secondary amine (D) can be obtained by reducing the amide (A) or byreacting the primary amine (B) with the compound (C) having a leavinggroup. (The secondary amine can be also synthesized using compounds withR¹ and R² reversed in the above chemical reaction formula.) Thesecondary amine (G) can be obtained by reacting the compound (E) havinga leaving group with the primary amine (F) similarly. The presentcompound [2] is obtained by reacting the primary amine (B) or thesecondary amine (D) with the primary amine (F) or the secondary amine(G) in the presence of the condensing agent (H) (for example,1,1′-carbonyldiimidazole).

The present compound [3] is obtained by reacting the primary amine (B)or the secondary amine (D) synthesized by the reaction route 1 with thecarboxylic acid (I) in the presence of a condensing agent (for example,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride).

The present compound [4] is obtained by reacting the primary amine (B)or the secondary amine (D) synthesized by the reaction route 1 with thealcohol (J) in the presence of a condensing agent (for example,N,N′-disuccinimidyl carbonate).

In the above-mentioned synthetic methods, when the, reactant has athiol, hydroxy or amino group in its molecule, these groups can beprotected with suitable protecting groups, if necessary, and theseprotecting groups can also be removed by the conventional method afterreaction. When the reactant has a carboxyl group in its molecule, thecarboxyl group can be esterified, if necessary, and the ester can alsobe converted into a carboxylic acid by hydrolysis or other generalmethods.

The compounds obtained by the above-mentioned synthetic methods can beconverted into the above-mentioned salts by the conventional method.

The inhibitory effects of TNF-α production were examined in order tostudy utility of the present compounds obtained by the above-mentionedsynthetic methods. Details will be described in the section of“Pharmacological test” below. Studying in vivo inhibitory effects onrelease of TNF-α caused by stimulation of lipopolysaccharide (LPS), thepresent compounds exhibited the excellent inhibitory effects of TNF-αproduction.

TNF-α production is known to be closely related to pathogenesis ofautoimmune diseases such as rheumatoid arthritis, Crohn's disease andsystemic lupus erythematosus, cachexia, acute infectious disease,allergy, pyrexia, anemia, diabetes and the like. Compounds which inhibitproduction of TNF-α like the present compounds are expected to be usefulfor treatment of these various diseases.

The present invention provides a method of inhibiting TNF-α production,a method of treating the autoimmune diseases and a method of treatingrheumatic diseases comprising administering to a patient a compositioncomprising an effective amount of the present compound or apharmacologically acceptable salts thereof and a pharmacologicallyacceptable additive.

The present compound can be administered orally or parenterally.Examples of dosage forms are tablets, capsules, granules, powders,injections and the like. The present compound can be formulated intopreparations by the conventional methods. For example, oral preparationssuch as tablets, capsules, granules and powders can be produced byadding optionally a diluent such as lactose, crystalline cellulose,starch or vegetable oil; a lubricant such as magnesium stearate or talc;a binder such as hydroxypropylcellulose or polyvinyl pyrrolidone; adisintegrator such as calcium carboxymethylcellulose or low-substitutedhydroxypropyl-methylcellulose; a coating agent such ashydroxypropylmethylcellulose, macrogol or silicone resin; or a filmforming agent such as gelatin film.

The dosage of the present compound can be selected suitably according tothe symptom, age, dosage form and the like. In case of the oralpreparation, the present compound can be administered once to severaltimes per day with a daily dose of 0.1 to 5000 mg, preferably 1 to 1000mg.

Examples of preparations of intermediates, examples of preparations andformulations of the present compounds and results of pharmacologicaltest are shown below. These examples do not limit the scope of theinvention, but are intended to make the invention more clearlyunderstandable.

BEST MODE FOR CARRYING OUT THE INVENTION [A] Preparation ofIntermediates PREPARATION EXAMPLE 1 2-(1-Adamantyl)-N-pentylethylaminehydrochloride (Intermediate No. 1-1)

Pentylamine (2.69 ml, 23.2 mmol), potassium carbonate (2.14 g, 15.5mmol) and sodium iodide (2.30 g, 15.3 mmol) were added to a solution of2-(1-adamantyl)ethyl methanesulfonate (2.07 g, 8.01 mmol) in ethanol(45.8 ml), and the mixture was refluxed for 17 hours. The reactionmixture was concentrated under reduced pressure, and the concentrate wasdiluted with chloroform (100 ml). This was washed with a 1 N aqueoussodium hydroxide solution (100 ml) and a saturated aqueous sodiumchloride solution (100 ml) successively, and the organic layer was driedover magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography. A 4 N solution of hydrogen chloride in ethyl acetate(3.1 ml) was added to a solution of the resulting free form (1.52 g,6.10 mmol) of the titled compound in ethyl acetate (0.50 ml). Theprecipitated solid was washed with ethyl acetate and filtered off togive 1.33 g (60%) of the titled compound.

IR(KBr): 2924, 2850, 2519, 1456 cm⁻¹

mp: 263.0-264.5° C.

The following compounds were obtained by a method similar to PreparationExample 1. The titled compounds were not sometimes isolated in the formof hydrochlorides.

N′-[2-(1-Adamantyl)ethyl]-N-(benzyloxycarbonyl)-N-methylethylenediamine(Intermediate No. 1-2)

IR(neat): 2901, 2844, 1704 cm⁻¹

2(1-Adamantyl)-N-(cyclopentylmethyl)ethylamine hydrochloride(Intermediate No. 1-3)

IR(KBr): 2907, 2847, 1452 cm⁻¹

mp: 300.0-310.0° C.

N′-[2-(1-Adamantyl)ethyl]-N-(t-butoxycarbonyl)-N-methylethylenediamine(Intermediate No. 1-4)

IR(neat): 3307, 2902, 2846, 1698 cm⁻¹

2,2′-Di(1-adamantyl)diethylamine hydrochloride (Intermediate No. 1-5)

IR(KBr): 2900, 2845, 2735, 2453 cm⁻¹

mp: 325° C.

2-(1-Adamantyl)-N-propylethylamine (Intermediate No. 1-6)

IR(neat): 3276, 2903, 2846, 1450 cm⁻¹

N′-[2-(1-Adamantyl)ethyl]-N,N-dimethylethylenediamine dihydrochloride(Intermediate No. 1-7)

IR(KBr): 3424, 2901, 2846, 2445 cm⁻¹

mp: 254.5-259.0° C.

2-(1-Adamantyl)-N-cyclopentylethylamine hydrochloride (Intermediate No.1-8)

IR(KBr): 2910, 2846, 2771, 2450 cm⁻¹

mp: 300-312° C.

2-(1-Adamantyl)-N-cyclopropylethylamine (Intermediate No. 1-9)

IR(neat): 3272, 2901, 2845 cm⁻¹

2-(1-Adamantyl)-N-(2-methoxyethyl)ethylamine hydrochloride (IntermediateNo. 1-10)

IR(KBr): 2909, 2846, 2792, 1451 cm⁻¹

mp: 278.5-281.5° C.

(1-Adamantyl)-N-(2-propynyl)ethylamine (Intermediate No. 1-11)

IR(neat): 2900, 2845, 1450 cm⁻¹

N-Pentyl-2-(2-pyridyl)ethylamine (Intermediate No. 1-12)

IR(neat): 3305, 2927, 2857, 1591 cm⁻¹

2-(1-Adamantyl)-N-benzylethylamine hydrochloride (Intermediate No. 1-13)

IR(KBr): 2900, 2846, 2750, 2528, 2468, 2372, 1585 cm⁻¹

mp: 264.0-265.0° C.

2-(1-Adamantyl)-N-furfurylethylamine hydrochloride (Intermediate No.1-14)

IR(KBr): 3456, 2903, 2846, 2741, 2426 cm⁻¹

mp: 225.0-233.0° C.

2-(1-Adamantyl)-N-butylethylamine (Intermediate No. 1-15)

IR(neat): 2903, 1683, 1450 cm⁻¹

Cyclohexyl-N-(2-thienyl)methylethylamine hydrochloride (Intermediate No.1-16) N-Pentylphenethylamine hydrochloride (Intermediate No. 1-17)

IR(KBr): 3028, 2957, 2786, 1456 cm⁻¹

mp: 260.0-285.0° C.

2-Cyclohexyl-N-butylethylamine hydrochloride (Intermediate No. 1-18)

IR(KBr): 2921, 2853, 2794, 2739, 2442, 1590, 1484, 1451 cm⁻¹

mp: 250° C. or higher

2-Cyclohexyl-N-pentylethylamine hydrochloride (Intermediate No. 1-19)

IR(KBr): 2924, 2793, 1451 cm⁻¹

mp: 250° C. or higher

N-(t-Butoxycarbonyl)-N′-(2-cyclohexylethyl)-N-methylethylenediamine(Intermediate No. 1-20)

IR(neat): 3350, 2923, 2850, 1697, 1481, 1449 cm⁻¹

N′-(2-Cyclohexylethyl)-N,N-dimethylethylenediamine (Intermediate No.1-21)

IR(neat): 3310, 2921, 2850, 2815, 1448 cm⁻¹

N-[2-(1-Adamantyl)ethyl]-3-(4-pyridyl)propylamine (Intermediate No.1-22)

IR(neat): 3291, 2902, 2845, 1602, 1450 cm⁻¹

2-(1-Adamantyl)-N-isopropylethylamine hydrochloride (Intermediate No.1-23)

IR(KBr): 2909, 2846, 2754, 2464, 1588, 1476, 1451 cm⁻¹

mp: 266.0-269.5° C.

N-(2-Piperidinoethyl)pentylamine (Intermediate No. 1-24)

IR(neat): 2932, 2854, 1466 cm⁻¹

2-(1-Adamantyl)-N-[(2-methylthiazol-4-yl)methyl]ethylamine (IntermediateNo. 1-25)

IR(neat): 2901, 2844, 1449 cm⁻¹

N-[2-(1-Adamantyl)ethyl]cinnamylamine (Intermediate No. 1-26)

IR(neat): 2901, 2845, 1449 cm⁻¹

N-[2-(1-Adamantyl)ethyl]-2-methyl-2-propenylamine (Intermediate No.1-27)

IR(neat): 2902, 2845, 1450 cm⁻¹

N-[2-(1-Adamantyl)ethyl]-3-methyl-2-butenylamine (Intermediate No. 1-28)

IR(neat): 2903, 2846, 1450 cm⁻¹

N-[2-(1-Adamantyl)ethyl]decylamine hydrochloride (Intermediate No. 1-29)

IR(KBr): 2926, 2849, 2778, 2469 cm⁻¹

mp: 204.0-208.5° C.

N-[2-(1-Adamantyl)ethyl]hexylamine hydrochloride (Intermediate No. 1-30)

IR(KBr): 2909, 2848, 2766, 2446 cm⁻¹

mp: 230.0-243.0° C.

2-(1-Adamantyl)-N-(benzyloxy)ethylamine (Intermediate No. 1-31)

IR(neat): 2901, 2846, 1452 cm⁻¹

2-(1-Adamantyl)-N-[(2-thienyl)methyl]ethylamine hydrochloride(Intermediate No. 1-32)

IR(KBr): 2908, 2846, 2757, 2426 cm⁻¹

mp: 257.0-260.0° C.

N-[2-(1-Adamantyl)ethyl]-2-butenylamine (Intermediate No. 1-33)

IR(neat): 2901, 1450 cm⁻¹

N-[2-(1-Adamantyl)ethyl]allylamine (Intermediate No. 1-34)

IR(neat): 2902, 1450 cm⁻¹

N-[2-(1-Adamantyl)ethyl]cyclopropylmethylamine (Intermediate No. 1-35)

IR(neat): 2901, 1450 cm⁻¹

N-[2-(1-Adamantyl)ethyl]-3,3,3-trifluoropropylamine hydrochloride(Intermediate No. 1-36)

IR(KBr): 2910, 2849, 2767, 2598, 2457 cm⁻¹

mp: 300.0-310.0° C.

1-[2-(1-Adamantyl)ethyl]-2-(t-butoxycarbonyl)hydrazine (Intermediate No.1-37)

IR(KBr): 3288, 2899, 1705 cm⁻¹

mp: 73.5-81.0° C.

N-(t-Butoxycarbonyl)-N-methyl-N′-phenethylethylenediamine (IntermediateNo. 1-38)

IR(neat): 3326, 3025, 2975, 2930, 1694, 1454 cm⁻¹

N-(t-Butoxycarbonyl)-N-methyl-N′-pentylethylnediamine (Intermediate No.1-39)

IR(neat): 2958, 2929, 1694, 1457 cm⁻¹

N-(Benzyloxycarbonyl)-N-methyl-N′-phenethylethylenediamine (IntermediateNo. 1-40)

IR(neat): 3309, 3027, 2936, 2824, 1698, 1454 cm⁻¹

N-(Benzyloxycarbonyl)-N-methyl-N′-pentylethylenediamine (IntermediateNo. 1-41)

IR(neat): 2928, 2858, 1703, 1455 cm⁻¹

2-Cyclohexyl-N-(2-methoxyethyl)ethylamine hydrochloride (IntermediateNo. 1-42)

IR(KBr): 2923, 2855, 2784, 2478, 2444 cm⁻¹

mp: 205.0-208.0° C.

N-Ethyl-3,4,5-trimethoxyphenethylamine (Intermediate No. 1-43)

IR(neat): 3300, 2936, 2828, 1588, 1508, 1457, 1419, 1331, 1236, 1126,1008 cm⁻¹

5-[2-(Isopentylamino)ethyl]imidazole dihydrochloride (Intermediate No.1-44)

IR(KBr): 2806, 2467, 1619, 1604, 1446, 1347, 1089, 914, 827, 735, 627,622 cm⁻¹

mp: 235.2-238.0° C.

N-Cyclohexyl-3,4-dimethoxyphenethylamine (Intermediate No. 1-45)

IR(neat): 2928, 2852, 1591, 1515, 1463, 1449, 1416, 1261, 1236, 1155,1139, 1029, 802, 761 cm⁻¹

bp: 170° C./210 Pa

N-Cyclopropyl-3,4,5-trimethoxyphenethylamine (Intermediate No. 1-46)

IR(neat): 3304, 2932, 2832, 1588, 1505, 1459, 1418, 1332, 1236, 1126,1009 cm⁻¹

N′-[2-(1-Adamantyl)ethyl]-N-(t-butoxycarbonyl)-N-methyl-1,3-propanediamine(Intermediate No. 1-47)

IR(neat): 3308, 2902, 2845, 1698, 1480 cm⁻¹

N-Cyclohexyl(phenyl)methyl-3-(4-methoxyphenyl)propylamine hydrochloride(Intermediate No. 1-48)

IR(KBr): 2928, 2857, 2765, 1592, 1510, 1455, 1230, 1064, 1033, 817 cm⁻¹

mp: 187.5-189.5° C.

N-Diphenylmethyl-3-phenylpropylamine (Intermediate No. 1-49)

IR(neat): 3024, 2931, 1601, 1493, 1452 cm⁻¹

N-Pentyl-3-phenylpropylamine hydrochloride (Intermediate No. 1-60)

IR(KBr): 3027, 2955, 2870, 2780, 2492, 2413 cm⁻¹

rmp: 230.0-238.0° C.

N-Acetyl-N′-[2-(1-adamantyl)ethyl]ethylenediamine hydrochloride(Intermediate No. 1-51)

IR(KBr): 2897, 2845, 2361, 1826, 1707, 1567 m⁻¹

mp: 245.0-247.0° C.

N-Isopentyl-3,3,3-trifluoropropylamine hydrochloride (Intermediate No.1-52)

IR(KBr): 2961, 2800, 1253, 1173 m⁻¹

mp: 288° C. or higher

N-[2-(1-Adamantyl)ethyl]-2,2,2-trifluoroethylamine hydrochloride(Intermediate No. 1-53)

IR(KBr): 2904, 2849, 1273, 1233, 1176, 1145 m⁻¹

mp: 263.0-265.0° C.

3-Cyclohexyl-N-propylpropylamine hydrochloride (Intermediate No. 1-54)

IR(KBr): 2924, 2854, 2779 m⁻¹

mp: 234.6-235.4° C.

N′-[3-(1-Adamantyl)propyl]-N-(t-butoxycarbonyl)-N-methylethylenediamine(Intermediate No. 1-55)

¹H-NMR (400 MHz, CDCl₃) δ 0.99-1.10 (m, 2H), 1.32-1.52 (m, 17H),1.55-1.65 (m, 4H), 1.70 (d, J=11.8 Hz, 3H), 1.93 (s, 3H), 2.58 (t, J=7.2Hz, 2H), 2.77 (br, 2H), 2.91 (s, 3H), 3.33 (br, 2H)

PREPARATION EXAMPLE 2 4-(3-Aminopropyl)pyridine (Intermediate No. 2-1)

N-[3-(4-Pyridyl)propyl]phthalimide (67.1 g, 252 mmol) was mixed withmethanol (504 ml) and hydrazine monohydrate (18.3 ml, 378 mmol), and themixture was refluxed for three hours. The reaction mixture was allowedto stand, then an insoluble matter was filtered out, and the filtratewas concentrated under reduced pressure. Chloroform (1 liter) and a 4 Naqueous sodium hydroxide solution (500 ml) were added to the residue,layers were separated, and the organic layer was dried over sodiumsulfate. The organic layer was concentrated under reduced pressure andthen distilled under reduced pressure to give 20.5 g (60%) of the titledcompound as a colorless oily matter.

IR(neat): 3362, 2933, 1603 cm⁻¹

bp: 76.0-79.0° C./40 Pa

The following compounds were obtained by a method similar to PreparationExample 2.

3-(4-Pyridyl)-2-propenylamine (Intermediate No. 2-2)

IR(neat): 3280, 3024, 1599 cm⁻¹

2-(4-Pyridyloxy)ethylamine (Intermediate No. 2-3)

IR(KBr): 3298, 3102, 1610, 1216, 1049 cm⁻¹

mp: 108.0-111.5° C.

3-(4-Quinolyl)-2-propenylamine (Intermediate No. 2-4)

IR(neat): 3270, 2944, 1585, 1568, 1508 cm⁻¹

PREPARATION EXAMPLE 3 2-(1-Adamantyl)-N-methylethylamine (IntermediateNo. 3-1)

A solution of 1-adamantaneacetic acid N-methylamide (1.54 g, 7.45 mmol)in tetrahydrofuran (15.0 ml) was added dropwise to a solution of lithiumaluminum hydride (569 mg, 15.0 mmol) in diethyl ether (34.0 ml) underice-cooling over five minutes. The mixture was refluxed for six hoursand then stirred under ice-cooling again. Ethyl acetate was added to thereaction mixture to treat excess lithium aluminum hydride, and then thewhole was extracted with 1 N hydrochloric acid (50 ml) twice. A 4 Naqueous sodium hydroxide solution was added to the extract to basify it,and the whole was extracted with diethyl ether (80 ml). The organiclayer was washed with a saturated aqueous sodium chloride solution (60ml) and dried over magnesium sulfate. The solvent was evaporated underreduced pressure to give 890 mg (66%) of the titled compound.

IR(neat): 2902, 2845, 1449 cm⁻¹

The following compounds were obtained by a method similar to PreparationExample 3. The compounds could also be converted into correspondinghydrochlorides with a 4 N solution of hydrogen chloride in ethylacetate.

2-(1-Adamantyl)-N-ethylethylamine hydrochloride (Intermediate No. 3-2)

IR(KBr): 2896, 2847, 2753, 2468, 1610 cm⁻¹

mp: 230-245° C.

N-Methyl-3-(4-pyridyl)propylamine (Intermediate No. 3-3)

IR(neat): 3292, 2934, 1602 cm⁻¹

1-Adamantyl-N-propylmethylamine hydrochloride (Intermediate No. 3-4)

IR(KBr): 2905, 1584, 1451 cm⁻¹

mp: 340° C.

2-(1-Adamantyl)-N-methylethylamine hydrochloride (Intermediate No. 3-5)

IR(KBr): 3422, 2900, 2846, 2676, 2450, 1630 cm⁻¹

mp: 200-220° C.

3-(1-Adamantyl)-N-propylpropylamine hydrochloride (Intermediate No. 3-6)

IR(KBr): 2899, 2467, 1449 cm⁻¹

mp: 159.5-162.0° C.

1-Adamantyl-N-pentylethylamine hydrochloride (Intermediate No. 3-7)

IR(KBr): 2916, 2603, 2509, 2418, 1477 cm⁻¹

mp: 170-235° C.

N-[3-(1-Adamantyl)propyl]pentylamine hydrochloride (Intermediate No.3-8)

IR(KBr): 2901, 2847, 1466, 1453 cm⁻¹

mp: 199-224° C.

N-[2-(1-Adamantyl)ethyl]-4,4,4-trifluorobutylamine hydrochloride(Intermediate No. 3-9)

IR(KBr): 3422, 2908, 2852, 2770, 2518, 1452, 1255, 1148 cm⁻¹

mp: 243-274° C.

N-[2-(1-Adamantyl)ethyl]-5,5,5-trifluoropentylamine (Intermediate No.3-10)

IR(neat): 2903, 2846, 1450, 1255, 1142 cm⁻¹

N-[3-(1-Adamantyl)propyl]butylamine hydrochloride (Intermediate No.3-11)

IR(KBr): 2904, 2847, 2756, 1453 cm⁻¹

mp: 275.0-276.8° C.

3-(1-Adamantyl)-N-(2,2,2-trifluoroethyl)propylamine hydrochloride(Intermediate No. 3-12)

IR(KBr): 2902, 2850, 2739, 1274, 1258, 1176, 1139 cm⁻¹

mp: 262.0-268.0° C.

4-(1-Adamantyl)-N-ethylbutylamine hydrochloride (Intermediate No. 3-13)

IR(KBr): 2901, 2847, 2457, 1451 cm⁻¹

mp: 224-230° C.

4-(1-Adamantyl)-N-propylbutylamine hydrochloride (Intermediate No. 3-14)

IR(KBr): 2899, 2848, 2751, 2410, 1451 cm⁻¹

mp: 234-249° C.

N-(1-Adamantyl)-N′-propylethylenediamine dihydrochloride (IntermediateNo. 3-15)

IR(KBr): 2927, 2719, 2508, 2429, 1471 cm⁻¹

mp: 288.5-289.5° C.

PREPARATION EXAMPLE 4 t-Butyl3-[N-[2-(1-adamantyl)ethyl]amino]propionate hydrochloride (IntermediateNo. 4-1)

2-(1-Adamantyl)ethylamine hydrochloride (1.0 g, 4.6 mmol) was dissolvedin ethanol (10 ml), and triethylamine (0.65 ml, 4.6 mmol) and t-butylacrylate (0.75 ml, 5.1 mmol) were added to the solution underice-cooling. Then, the temperature was raised to room temperature, andthe mixture was stirred overnight. The reaction mixture was concentratedunder reduced pressure, a 1 N aqueous sodium hydroxide solution (30 ml)and ethyl acetate (50 ml) were added to the residue, and layers wereseparated. The ethyl acetate layer was washed with water (50 ml) and asaturated aqueous sodium chloride solution (50 ml) successively anddried over anhydrous magnesium sulfate. The ethyl acetate layer wasconcentrated under reduced pressure, and the concentrate was purified bysilica gel column chromatography. The resulting oily matter (0.50 g, 1.6mmol) was dissolved in diethyl ether (20 ml), and a 4 N solution ofhydrogen chloride in ethyl acetate (1.0 ml, 4.0 mmol) was added theretoto precipitate a solid. This solid was filtered off with diethyl etherto give 0.33 g (23%) of the titled compound.

IR(KBr): 2902, 2846, 1733, 1166 cm⁻¹

mp: 210° C.

The following compounds were obtained by a method similar to PreparationExample 4. The titled compounds were not sometimes isolated in the formof hydrochlorides.

Methyl 3-[N-(2-cyclohexylethyl)amino]propionate hydrochloride(Intermediate No. 4-2)

IR(KBr): 2924, 2853, 2792, 1736, 1455, 1439 cm⁻¹

mp: 185.0-187.5° C.

t-Butyl 3-[N-(2-cyclohexylethyl)amino]propionate (Intermediate No. 4-3)

IR(neat): 2977, 2922, 2850, 1728, 1449 cm⁻¹

t-Butyl 3-[N-[3-(4-pyridyl)propyl]amino]propionate hydrochloride(Intermediate No. 4-4)

IR(neat): 3322, 2977, 2933, 1724, 1602, 1367, 1153 cm⁻¹

PRODUCTION EXAMPLE 5 5-(4-Pyridyl)valeric acid (Intermediate No. 5-1)

N,N-Dimethylformamide (17 ml) was added to a mixture of(benzyloxycarbonylmethyl)triphenylphosphonium bromide (4.60 g, 9.36mmol) and β-(4-pyridyl)acrolein oxalate (1.90 g, 8.51 mmol), and thewhole was stirred under ice-cooling. Potassium carbonate (4.70 g, 34.0mmol) was added thereto, and the temperature was raised to roomtemperature. The whole was stirred overnight, then diluted with ethylacetate (100 ml) and washed with water (100 ml) twice and saturatedbrine (50 ml) successively. The organic layer was dried over sodiumsulfate, and ethyl acetate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to give 2.29 g(quantitatively) of 5-(4-pyridyl)valeric acid-2,4-diene benzyl ester asa pale yellow oily matter.

Next, methanol (42 ml) and acetic acid (1.0 ml, 18 mmol) were added to5-(4-pyridyl)valeric acid-2,4-diene benzyl ester (2.25 g, 8.48 mmol),and a nitrogen gas was bubbled through the mixture for ten minutes.Palladium hydroxide on carbon (catalytic amount) was added to themixture, and the whole was stirred under a hydrogen atmosphere at roomtemperature overnight. An insoluble matter was filtered out by Celitefiltration, and the filtrate was concentrated under reduced pressure.Ethyl acetate (50 ml) was added to the solidified residue, and themixture was stirred at room temperature for three hours. Crystals werefiltered off to give 1.00 g (66%) of the titled compound as pale yellowcrystals.

IR(KBr): 2943, 1719, 1636, 1605 cm⁻¹

mp: 155.0-180.0° C.

PREPARATION EXAMPLE 6 3-[N-(2-Cyclohexylethyl)amino]propionamidehydrochloride (Intermediate No. 6-1)

Trifluoroacetic acid (6 ml) was added to t-butyl3-[N-(2-cyclohexylethyl)amino]propionate (Intermediate No. 4-3, 2.0 g,7.8 mmol) under ice-cooling. The mixture was stirred overnight, and thenconcentrated under reduced pressure. A 4 N solution of hydrogen chloridein ethyl acetate was added to the residue, and the whole wasconcentrated under reduced pressure, and then the resulting crystalswere filtered off with diethyl ether to give 1.5 g (96%) of3-[N-(2-cyclohexylethyl)amino]propionic acid hydrochloride.

Next, tetrahydrofuran (8 ml) was added to3-[N-(2-cyclohexylethyl)amino]propionic acid hydrochloride (1.0 g, 4.2mmol), and the mixture was stirred at room temperature. Di-t-butylcarbonate (1.1 g, 5.1 mmol) and triethylamine (1.3 ml, 9.3 mmol) wereadded to the mixture, the whole was stirred overnight, and then a 5%aqueous citric acid solution (10 ml) was added to the reaction mixture.The whole was extracted with chloroform (60 ml), and the organic layerwas washed with saturated brine (20 ml). The organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give 0.79 g(62%) of 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionicacid as a colorless oily matter.

Next, anhydrous tetrahydrofuran (7 ml) was added to3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid (0.59g, 2.0 mmol), and the mixture was stirred at −78° C. N-Methylmorpholine(0.22 ml, 2.0 mmol) and then a solution of isobutyl chloroformate (0.38ml, 2.9 mmol) in tetrahydrofuran (3 ml) were added to the mixture. Afterone hour, a 28% aqueous ammonia solution (6.0 ml, 9.8 mmol) was addedthereto, and the whole was stirred for 1.5 hours. Chloroform (50 ml) wasadded to the reaction mixture, the temperature was raised to roomtemperature, and the whole was washed with a saturated aqueous sodiumhydrogencarbonate solution (20 ml) and saturated brine (20 ml)successively. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give 0.34 g (58%) of3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide ascolorless crystals.

Next, a 4 N solution of hydrogen chloride in 1,4-dioxane (3.1 ml) wasadded to 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide(0.37 g, 1.2 mmol), and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,diisopropyl ether was added to the resulting solid, and the solid wasfiltered off to give 0.30 g (quantitatively) of the titled compound ascolorless crystals.

IR(KBr): 3386, 3196, 2921, 2852, 2808, 1705, 1656, 1452 cm⁻¹

mp: 165.0° C.

PREPARATION EXAMPLE 7 Di-5-hexenylamine (Intermediate No. 7-1)

N,N-Dimethylformamide (28 ml) was added to 3-aminopropionitrile (0.98 g,14 mmol), and the mixture was stirred at room temperature.6-Bromo-1-hexene (5.0 g, 31 mmol), sodium iodide (11 g, 73 mmol) andpotassium carbonate (5.8 g, 42 mmol) were added to the mixture, and thewhole was stirred overnight. The reaction mixture was diluted withdiethyl ether (100 ml), and the whole was washed with water (100 ml,twice) and saturated brine (50 ml) successively. The organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give 2.2 g(66%) of 3-(di-5-hexenyl)aminopropionitrile as a colorless oily matter.

Next, ethanol (8.6 ml) and potassium hydroxide (0.85 g, 13 mmol) wereadded to 3-(di-5-hexenyl)aminopropionitrile (2.0 g, 8.6 mmol), and themixture was refluxed for 7.5 hours. The reaction mixture was allowed tostand, and then water (150 ml) and chloroform (150 ml) were added to thereaction mixture. Layers were separated, and the organic layer was driedover sodium sulfate. The organic layer was concentrated under reducedpressure, and the residue was purified by basic silica gel columnchromatography to give 0.32 g (21%) of the titled compound as a paleyellow oily matter.

IR(neat): 3076, 2976, 2928, 2856, 1679, 1640 cm⁻¹

The following compound was obtained by a method similar to PreparationExample 7.

Di-7-octenylamine (Intermediate No. 7-2)

IR(neat): 3075, 2976, 2926, 2854, 1640 cm⁻¹

PREPARATION EXAMPLE 8 N-[2-(1-Adamantyloxy)ethyl]propylaminehydrochloride (Intermediate No. 8-1)

2-(Propylamino)ethanol (2.4 g, 23 mmol) was mixed with 1-bromoadamantane(0.50 g, 2.3 mmol) and triethylamine (0.32 ml, 2.3 mmol), and themixture was stirred at an external temperature of 100° C. for two hours,at 130° C. for five hours and at 150° C. for three hours. The reactionmixture was allowed to stand, then ethyl acetate (50 ml) was added tothe reaction mixture, and the whole was washed with water (50 ml) twiceand saturated brine (30 ml) successively. The organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography, a 4 N solution ofhydrogen chloride in ethyl acetate (2 ml) was added to the separatedsubstance, and the whole was concentrated under reduced pressure. Theresulting crystals were filtered off with ethyl acetate to give 0.16 g(25%) of the titled compound as colorless crystals.

IR(KBr): 3544, 2907, 2502, 1584 cm⁻¹

mp: 232.0-232.7° C.

PREPARATION EXAMPLE 9 2-Propylaminoacetic acid N-(1-adamantyl)amide(Intermediate No. 9-1)

Ethanol (36 ml) was added to bromoacetic acid (5.00 g, 36.0 mmol), andthe mixture was stirred under ice-cold water-cooling. Propylamine (14.8ml, 180 mmol) was added to the mixture over one minute, and then thewhole was stirred at an external temperature of 80° C. for 2.5 hours. A4 N aqueous sodium hydroxide solution (27 ml) was added thereto, and thewhole was concentrated under reduced pressure. Then, water (27 ml) andtetrahydrofuran (30 ml) were added to the concentrate, and the mixturewas stirred at room temperature. A solution of di-t-butyl carbonate(9.43 g, 43.2 mmol) in tetrahydrofuran (6 ml) was added to the mixture,and after 15 minutes, citric acid monohydrate was added to the reactionmixture to acidify it weakly. The whole was extracted with ethyl acetate(150 ml), and the organic layer was washed with water (100 ml) andsaturated brine (50 ml) successively. The organic layer was dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give 5.06 g (65%) of2-[N -(t-butoxycarbonyl)-N-propylamino]acetic acid as a colorless solid.

Next, methylene chloride (208 ml) was added to a mixture of2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol)and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred atroom temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) andthen O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and thewhole was stirred overnight. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography to give 7.88 g (quantitatively) of2-[N′-(t-butoxycarbonyl)-N′-propylamino]acetic acid N-(1-adamantyl)amideas a colorless oily matter. The obtained oily matter solidified at roomtemperature.

Next, a 4 N solution of hydrogen chloride in ethyl acetate (55 ml, 0.22mol) was added to 2-[N′-(t-butoxycarbonyl)-N′-propylamino]acetic acidN-(1-adamantyl)amide (7.68 g, 21.9 mmol), and the mixture was stirred atroom temperature for one hour. The resulting crystals were filtered offwith ethyl acetate and washed with ethyl acetate to give 5.97 g (95%) ofthe titled compound as colorless crystals.

IR(KBr): 3272, 2906, 2848, 2589, 1676, 1562 cm⁻¹

mp: 278.0-279.2° C.

PREPARATION EXAMPLE 10 N-(t-Butoxycarbonyl)-2-(4-pyridyloxy)ethylamine(Intermediate No. 10-1)

Di-t-butyl dicarbonate (380 mg, 1.74 mmol) and triethylamine (240 μl,1.74 mmol) were added to a solution of the Intermediate No. 2-4 (200 mg,1.45 mmol) in tetrahydrofuran (5 ml) under ice-cooling, the temperaturewas raised to room temperature, and the mixture was stirred for 25minutes. The solvent was evaporated under reduced pressure from thereaction mixture, and the residue was distributed with ethyl acetate (50ml) and a saturated aqueous sodium hydrogencarbonate solution (50 ml).The aqueous layer was further extracted with chloroform (50 ml), and thecombined organic layer was dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the resulting residuewas purified by silica gel column chromatography to give 70 mg (20.2%)of the titled compound.

IR(neat): 3230, 2976, 1706, 1596 cm⁻¹

PREPARATION EXAMPLE 11 (RS)-2-Methyl-3-(4-pyridyl)propylamine(Intermediate No. 11-1)

N,N-Dimethylformamide (143 ml) was added to sodium hydride (5.36 g, 134mmol) under a nitrogen atmosphere, and the mixture was stirred underice-cooling. A solution of diethyl methylmalonate (11.7 g, 67.1 mmol) inN,N-dimethylformamide (40 ml) was added dropwise to the mixture overfive minutes, after ten minutes, 4-chloropicolyl hydrochloride (10.0 g,61.0 mmol) was added thereto little by little over five minutes, and thetemperature was raised to room temperature. After one hour, a saturatedaqueous sodium hydrogencarbonate solution (500 ml) was added to thereaction mixture, and the whole was extracted with diethyl ether (400ml). The organic layer was washed with water (100 ml) and saturatedbrine (50 ml) and dried over magnesium sulfate. The organic layer wasconcentrated under reduced pressure to give 17.2 g (quantitatively,containing sodium hydride oil) of diethyl2-methyl-2-(4-pyridylmethyl)malonate as a brown oily matter.

Next, 6 N hydrochloric acid (96.8 ml, 581 mmol) was added to diethyl2-methyl-2-(4-pyridylmethyl)malonate (17.2 g, 64.6 mmol), and themixture was refluxed overnight. The reaction mixture was allowed tostand, then washed with hexane (100 ml) to remove sodium hydride oilcontained in diethyl 2-methyl-2-(4-pyridylmethyl)malonate, andconcentrated under reduced pressure. The resulting crystals werefiltered off with ethyl acetate to give 10.7 g (82%) of2-methyl-3-(4-pyridyl)propionic acid as pale pink crystals.

Next, chloroform (8 ml), thionyl chloride (2.2 ml, 30.6 mmol) andN,N-dimethylformamide (one drop) were added to2-methyl-3-(4-pyridyl)propionic acid (1.69 g, 10.2 mmol), and themixture was refluxed with stirring for one hour. The reaction mixturewas concentrated under reduced pressure, chloroform (8 ml) was added tothe concentrate, and the mixture was added slowly to a 28% aqueousammonia solution stirred under ice-cooling. After ten minutes, thetemperature was raised to room temperature, and the whole was stirredovernight. The reaction mixture was concentrated under reduced pressure,ethyl acetate (100 ml) was added to the concentrate, and the resultinginsoluble matter was filtered out. The filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography, and the resulting crystals were filtered off withdiethyl ether to give 0.72 g (43%) of 2-methyl-3-(4-pyridyl)propionamideas pale yellow crystals.

Next, anhydrous diethyl ether (20 ml) was added to lithium aluminumhydride (0.45 g, 12 mmol) under a nitrogen atmosphere, and the mixturewas stirred under ice-cooling. A solution of2-methyl-3-(4-pyridyl)propionamide (0.68 g, 4.1 mmol) in anhydrousmethylene chloride (20 ml) was added dropwise to the mixture over fiveminutes, the temperature was raised to room temperature, and the wholewas stirred overnight. The reaction mixture was cooled with ice again,ethyl acetate (5 ml) was added slowly to the reaction mixture, and thena 1 N aqueous sodium hydroxide solution was added thereto first slowly(total 100 ml). The whole was extracted with chloroform (100 ml), andthe organic layer was dried over sodium sulfate and concentrated underreduced pressure to give 0.56 g (90%) of the titled compound as a paleyellow oily matter.

IR(neat): 3293, 2957, 2925, 1602 cm⁻¹

The following compounds were obtained by a method similar to PreparationExample 11. Optically active substances could be obtained by opticalresolution with an optically active acid.

2-(4-Pyridylmethyl)butylamine (Intermediate No. 11-2)

IR(neat): 3296, 3025, 2960, 2874, 1602 cm⁻¹

2-Benzyl-3-(4-pyridyl)propylamine (Intermediate No. 11-3)

IR(neat): 3296, 3062, 3025, 1602 cm⁻¹

2,2-Bis(4-pyridylmethyl)ethylamine (Intermediate No. 11-4)

IR(neat): 3290, 3026, 2924, 1602, 1557 cm⁻¹

(−)-2-Methyl-3-(4-pyridyl)propylamine (Intermediate No. 11-5)

IR(neat): 3362, 3301, 2958, 1603 cm⁻¹

[α]²⁰ _(D): −10.6° (MeOH, C 1.0)

(+)-2-Methyl-3-(4-pyridyl)propylamine (Intermediate No. 11-6)

IR(neat): 3362, 3294, 2958, 1603 cm⁻¹

[α]²⁰ _(D): +9.9° (MeOH, C 1.0)

PREPARATION EXAMPLE 12 3-(4-Quinolyl)propylamine (Intermediate No. 12-1)

A catalytic amount of 10% palladium on carbon was added to a solution of3-(4-quinolyl)-2-propenylamine (Intermediate No. 2-4) (188 mg, 1.02mmol) obtained in Preparation Example 2 in methanol (3 ml) at roomtemperature under a nitrogen atmosphere, and the mixture was stirredunder a hydrogen atmosphere overnight. The reaction mixture was filteredwith Celite, the solvent was evaporated under reduced pressure, and theresulting residue was distributed with ethyl acetate (30 ml) and asaturated aqueous ammonium chloride solution (30 ml). A 4 N aqueoussodium hydroxide solution (30 ml) was added to the aqueous layer, thewhole was extracted with chloroform (100 ml), and the obtained organiclayer was dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure to give 145 mg (76.3%) of the titledcompound.

IR(neat): 3350, 2938, 1591, 1510 cm⁻¹

PREPARATION EXAMPLE 13 3-(4-Pyridyl)butylamine (Intermediate No. 13-1)

N,N-Dimethylformamide (33 ml) was added to a mixture of 4-acetylpyridine(2.00 g, 16.5 mmol) and (benzyloxycarbonyl)methyltriphenylphosphoniumbromide (8.94 g, 18.2 mmol), and the whole was stirred underice-cooling. Potassium carbonate (9.12 g, 66.0 mmol) was added thereto,the external temperature was raised to 70° C., and the whole was stirredovernight. The reaction mixture was diluted with diethyl ether (100 ml),and the whole was washed with water (100 ml, twice) and saturated brine(50 ml) successively. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to give 1.77 g (42%: mixture of E formand Z form) of benzyl 3-(4-pyridyl)-2-butenoate as a pale yellow oilymatter.

Next, methanol (31 ml) and acetic acid (0.71 ml, 12.4 mmol) were addedto benzyl 3-(4-pyridyl)-2-butenoate (1.75 g, 6.20 mmol), and a nitrogengas was bubbled through the mixture at room temperature for 10 minutes.A catalytic amount of 10% palladium on carbon was added to the mixture,and the whole was stirred under a hydrogen atmosphere at roomtemperature overnight. An insoluble matter was filtered out, and thefiltrate was concentrated under reduced pressure. The resulting crystalswere filtered off with acetone to give 0.61 g (60%) of3-(4-pyridyl)butyric acid as pale yellow crystals.

Next, chloroform (5 ml), thionyl chloride (0.80 ml, 11 mmol) andN,N-dimethylformamide (one drop) were added to 3-(4-pyridyl)butyric acid(0.60 g, 3.6 mmol), and the mixture was refluxed with stirring for onehour. The reaction mixture was concentrated under reduced pressure,chloroform (5 ml) was added to the concentrate, and the whole was addedslowly to a saturated ammonia/tetrahydrofuran solution (5 ml) stirredunder ice-cooling. After 2.5 hours, an insoluble matter was filteredout, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give 0.34 gof a mixture of 3-(4-pyridyl)butyramide and its olefin oxide as paleyellow-crystals.

Next, anhydrous ether (8 ml) was added to lithium aluminum hydride (0.16g, 4.2 mmol) under a nitrogen atmosphere, and the mixture was stirredunder ice-cooling. A solution of 3-(4-pyridyl)butyramide (0.22 g, 1.4mmol) in anhydrous methylene chloride (8 ml) was added dropwise to themixture over two minutes, the temperature was raised to roomtemperature, and the whole was stirred overnight. Ethyl acetate (1 ml)and a 1 N aqueous sodium hydroxide solution (20 ml) were added to thereaction mixture, and the whole was extracted with chloroform (60 ml).The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give 0.15 g (75%) of the titled compound asa pale yellow oily matter.

IR(neat): 3350, 2963, 2873, 1601 cm⁻¹

PREPARATION EXAMPLE 14 N-(4-Pyridyl)ethylenediamine (Intermediate No.14-1)

Ethylenediamine (10.4 ml, 155 mmol) was added to 4-bromopyridinehydrochloride (3.00 g, 15.5 mmol) under a nitrogen atmosphere, and themixture was refluxed for 1.5 hours. The temperature was cooled to roomtemperature, potassium carbonate (8.57 g, 62.0 mmol) was added to thereaction mixture, and the whole was stirred for 10 minutes. Then, thesolid was filtered out and washed with toluene and 2-propanolsuccessively. The filtrate was concentrated under reduced pressure, theresidue was purified by basic silica gel column chromatography, and theresulting solid was filtered off with diisopropyl ether to give 1.63 g(77%) of the titled compound as a pale yellow solid.

IR(KBr): 3320, 3240, 3028, 2930, 1615 cm⁻¹

mp: 114.0-116.5° C.

PREPARATION EXAMPLE 15 4-(3-Aminobutyl)pyridine (Intermediate No. 15-1)

Anhydrous N,N-dimethylformamide (41 ml) was added to sodium hydride(2.81 g, 70.3 mmol) under a nitrogen atmosphere, and the mixture wasstirred under ice-cold water-cooling. A solution of t-butyl acetoacetate(6.33 g, 40.0 mmol) in N,N-dimethylformamide (20 ml) was added dropwiseto the mixture over 10 minutes, after 10 minutes,4-(chloromethyl)pyridine hydrochloride (5.00 g, 30.5 mmol) was addedthereto little by little under a nitrogen stream over three minutes, andthe temperature was raised to room temperature. After two hours, asaturated aqueous sodium hydrogencarbonate solution (150 ml) was addedto the reaction mixture, and the whole was extracted with ethyl acetate(100 ml). The organic layer was washed with water (100 ml) and saturatedbrine (50 ml) successively and dried over anhydrous sodium sulfate. Theorganic layer was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography to give 1.34 g (18%) ofethyl 2-acetyl-3-(4-pyridyl)propionate as a pale yellow oily matter.

Next, 6 N hydrochloric acid (8 ml) was added to ethyl2-acetyl-3-(4-pyridyl)propionate (1.20 g, 4.81 mmol), and the mixturewas refluxed for 1.5 hours. The reaction mixture was concentrated underreduced pressure, 2-propanol (10 ml) was added to the concentrate, andthe whole was concentrated under reduced pressure again. Ethyl acetatewas added to the resulting solid, and the solid was filtered off to give0.79 g (89%) of 4-(4-pyridyl)-2-butanone as a pale yellow solid.

Next, water (12 ml) and tetrahydrofuran (1.2 ml) were added to4-(4-pyridyl)-2-butanone (736 mg, 3.96 mmol), and the mixture wasstirred at room temperature. Sodium carbonate (483 mg, 4.56 mmol) andhydroxylamine hydrochloride (358 mg, 5.15 mmol) were added to themixture, and the whole was stirred for 1.5 hours and then diluted withethyl acetate (50 ml). Sodium hydrogencarbonate was added thereto,layers were separated, and the organic layer was washed with saturatedbrine (10 ml). The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. Cyclohexane was added to theresulting crystals, and the crystals were filtered off to give 584 mg(90%) of 4-(4-pyridyl)-2-butanoneoxime as pale yellow crystals.

Next, anhydrous ether (19 ml) was added to lithium aluminum hydride (257mg, 6.77 mmol) under a nitrogen atmosphere, and the mixture was stirredunder ice-cooling. A solution of 4-(4-pyridyl)-2-butanoneoxime (556 mg,3.38 mmol) in ether (15 ml) was added dropwise to the mixture over sevenminutes, then the temperature was raised to room temperature, and thewhole was refluxed overnight. Further, the whole was refluxed for twodays and then stirred under ice-cooling. Ethyl acetate was added slowlyto the reaction mixture, and then a 1 N aqueous sodium hydroxidesolution was added thereto (first slowly, total 20 ml). Chloroform (80ml) was added thereto, and an insoluble matter was filtered out withCelite. Layers were separated, and the chloroform layer was concentratedunder reduced pressure. The residue was combined with the aqueous layer,tetrahydrofuran (20 ml) was added thereto, and the whole was stirred atroom temperature. Di-t-butyl carbonate (1.48 g, 6.78 mmol) was addedthereto, and the whole was stirred overnight. The whole was extractedwith chloroform (50 ml), and the organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography. A 4 N solution ofhydrogen chloride in ethyl acetate (3 ml) and ethanol (1 ml) were addedto the residue, and the mixture was stirred at room temperature. Afterthree hours, the reaction mixture was concentrated under reducedpressure. Chloroform (5 ml), methanol (5 ml) and triethylamine (1 ml)were added to the residue, and the mixture was concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography to give 161 mg (32%) of the titled compound as a brownoily matter.

IR(neat): 3354, 3280, 2958, 2925, 2866, 1602 cm⁻¹

The following compounds were obtained by a method similar to PreparationExample 15.

1,2-Dimethyl-3-(4-pyridyl)propylamine (Intermediate No. 15-2)

IR(neat): 3360, 3287, 2963, 2930, 2876, 1602 cm⁻¹

1-Ethyl-3-(4-pyridyl)propylamine (Intermediate No. 15-3)

IR(neat): 3357, 2963, 2934, 2875, 1605 cm⁻¹

PREPARATION EXAMPLE 16 2,2-Dimethyl-3-(4-pyridyl)propylamine(Intermediate No. 16-1)

A solution of diisopropylamine (10.0 ml, 71.5 mmol) in tetrahydrofuran(150 ml) was cooled to −78° C. under a nitrogen atmosphere, and a 1.6 Nsolution of butyllithium in hexane was added dropwise thereto over 10minutes. The mixture was cooled with ice-cold water for 20 minutes andthen cooled to −78° C. again, and isobutyronitrile. (3.03 ml, 33.3 mmol)was added dropwise to the mixture over five minutes. Further,4-pyridinecarboxyaldehyde (3.18 ml, 33.3 mmol) was added dropwisethereto over five minutes, and the whole was stirred for one hour 20minutes. Water (100 ml) was added to the reaction mixture, and the wholewas extracted with ethyl acetate (200 ml) by using a continuousextracting apparatus for three days. The obtained organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting solid was filtered off with diethyl ether togive 4.20 g (71.6%) of 3-hydroxy-2,2-dimethyl-3-(4-pyridyl)propionitrileas a colorless solid.

Triethylamine (1.57 ml, 11.3 mmol) was added to a solution of3-hydroxy-2,2-dimethyl-3-(4-pyridylpropionitrile (1.00 g, 5.67 mmol) indichloromethane (20 ml) at room temperature. Further, p-toluenesulfonylchloride (1.30 g, 6.80 mmol) was added to the mixture, and the whole waswarmed at 50° C. with stirring for three days. The reaction mixture wasallowed to stand and then concentrated under reduced pressure, and theconcentrate was purified by silica gel column chromatography to give 699mg (37.4%) of2,2-dimethyl-3-(4-pyridyl)-3-(p-tolylsulfonyloxy)propionitrile as a paleyellow solid.

Anhydrous diethyl ether (10 ml) was dropwise to lithium aluminum hydride(345 mg, 9.10 mmol) under a nitrogen atmosphere and ice-coldwater-cooling. Then, a solution of2,2-dimethyl-3-(4-pyridyl)-3-(p-tolylsulfonyloxy)propionitrile (600 mg,1.82 mmol) in tetrahydrofuran (10 ml) was added dropwise to the mixture.The whole was stirred at room temperature overnight, and water (324 μl),a 15% aqueous sodium hydroxide solution (324 μl) and water (972 μl) wereadded successively to the reaction mixture while stirring it vigorouslyunder ice-cold water-cooling. The organic layer was dried over anhydrousmagnesium sulfate and-concentrated under reduced pressure, and theconcentrate was purified by silica gel column chromatography to give thetitled compound (83.0 mg, 0.505 mmol, 28%) as a pale yellow oily matter.

IR(neat): 3290, 3074, 2960, 1652, 1602, 1417 cm⁻¹

PREPARATION EXAMPLE 17 (RS)-2-Methyl-3-(4-pyridyl)propanol (IntermediateNo. 17-1)

2-Methyl-3-(4-pyridyl)propionic acid (136 g, 0.676 ml) obtained by thesynthetic process of Preparation Example 11 was dissolved intetrahydrofuran (1500 ml), and sodium borohydride (56.2 g, 1.49 mol) wasadded to the solution under ice-cold water-cooling. After 30 minutes, amixed liquid of iodine (85.8 g, 0.338 mol) and tetrahydrofuran (500 ml)was added dropwise to the mixture-under ice-cold water-cooling, and thetemperature was raised to room temperature. After two hours, thereaction mixture was cooled with ice-cold water, and a saturated aqueoussodium hydrogencarbonate solution (100 ml) was added dropwise to thereaction mixture. A saturated aqueous sodium chloride solution (900 ml)and water (400 ml) were added thereto, and the whole was extracted with-chloroform (1 liter×2). The organic layer was washed with a 0.01%aqueous sodium thiosulfate solution (1 liter) and a saturated aqueoussodium chloride solution (500 ml) successively, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give 127.1g (quantitatively) of the titled compound as a yellow oily matter.

IR(neat): 3292, 2928, 1606, 1558, 1419 cm⁻¹

PREPARATION EXAMPLE 183-(t-Butyldiphenylsilyloxy)-3-(4-pyridyl)propylamine (Intermediate No.18-1)

Diisopropylamine (1.98 g, 19.6 mmol) was added dropwise to a solution ofa butyllithium/hexane solution (10.5 ml, 16.8 mmol) in anhydroustetrahydrofuran (20 ml) at −80° C. over five minutes, the temperaturewas raised to 0° C., and the mixture was stirred for 30 minutes. Themixture was cooled to −80° C. again, then acetonitrile (573 mg, 14.0mmol) was added dropwise to the mixture over seven minutes, and after 20minutes, 4-pyridinecarboxyaldehyde (758 mg, 7.08 mmol) was addeddropwise thereto over 10 minutes. After 50 minutes, a saturated aqueousammonium chloride solution (20 ml) was added to the reaction mixture,and the temperature was raised to room temperature. The whole wascontinuously extracted (ethyl acetate and water) for four days. Theorganic layer was dried over anhydrous magnesium sulfate, the solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give3-hydroxy-3-(4-pyridyl)propionitrile (666 mg, colorless crystals,63.5%).

Next, imidazole (4.60 g, 67.5 mmol) and N,N-dimethylformamide (30 ml)were added to the obtained 3-hydroxy-3-(4-pyridyl)propionitrile (1.00 g,6.75 mmol), and the mixture was stirred at room temperature.t-Butyldiphenylchlorosilane (2.23 g, 8.10 mmol) was added to themixture, and the whole was stirred for one day and further stirred at anexternal temperature of 50° C. for three hours. Ethyl acetate (50 ml)and ether (50 ml) were added to the reaction mixture, the whole waswashed with water (20 ml) three times and saturated brine (30 ml)successively, and the organic layer was dried over anhydrous magnesiumsulfate. The organic layer was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography to give2.58 g (98.9%) of 3-(t-butyldiphenylsiloxy)-3-(4-pyridyl)propionitrileas a colorless oily matter.

Lithium aluminum hydride (299 mg, 7.87 mmol) was suspended in anhydrousdiethyl ether (10 ml) under a nitrogen atmosphere, and a solution of theobtained 3-(t-butyldiphenylsiloxy)-3-(4-pyridyl)propionitrile (1.00 g,2.59 mmol) in anhydrous diethyl ether (15 ml) was added dropwise to thesuspension under ice-cooling with stirring over eight minutes. Thetemperature was raised to room temperature, and the mixture was stirredfor 75 minutes. The reaction mixture was cooled with ice, ethyl acetate(15 ml) was added to the reaction mixture, and water (0.28 ml), a 15%aqueous sodium hydroxide solution (0.28 ml) and water (0.85 ml) wereadded thereto successively. The temperature was raised to roomtemperature, and the whole was stirred for 10 minutes. The reactionmixture was dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the titled compound (180.0 mg,yellow oily matter, 17.8%).

IR(neat): 3286, 3071, 2932, 2858, 1601, 1428 cm⁻¹

The following compound was obtained by a method similar to PreparationExample 18.

3-(t-Butyldimethylsilyloxy)-3-(4-pyridyl)propylamine (Intermediate No.18-2) PREPARATION EXAMPLE 19 N-[2-(1-Adamantyl)ethyl]-2-butynylamine(Intermediate No. 19-1)

Dimethyl sulfoxide (60 ml) and triethylamine (8.4 ml, 60 mmol) wereadded to 2-butyn-1-ol (3.0 ml, 40 ml), and the mixture was stirred underice-cold water-cooling. A sulfur trioxide-pyridine complex (4.2 g, 26mmol) was added to the mixture, after 15 minutes, a sulfurtrioxide-pyridine complex (5.1 g, 32 mmol) was further added thereto,and the whole was stirred for 1.5 hours. Water (40 ml) was added to thereaction mixture, and the whole was extracted with methylene chloride(40 ml) twice. The organic layer was washed with 1 N hydrochloric acid(30 ml) twice and water (40 ml) twice and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to give 1.0 g(37%) of 2-butynal as a brown oily matter.

Next, 2-(1-adamantyl)ethylamine hydrochloride (2.0 g, 9.3 mmol) wasdistributed with chloroform (30 ml) and a 1 N aqueous sodium hydroxidesolution (40 ml), and the organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give2-(1-adamantyl)ethylamine. Methanol (15 ml) and triethylamine (2.6 ml,19 mmol) were added to 2-(1-adamantyl)ethylamine, and the mixture wasstirred at room temperature. Then, a solution of 2-butynal (0.80 g, 12mmol) obtained by the above-mentioned reaction in methanol (10 ml) wasadded to the mixture, and after three hours, sodium borohydride (1.9 g,50 mmol) was added thereto under ice-cold water-cooling. After one hour,water (40 ml) was added to the reaction mixture, and the whole wasextracted with chloroform (60 ml). The organic layer was washed withsaturated brine (40 ml) and dried over anhydrous magnesium sulfate. Theorganic layer was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography to give 0.48 g (22%) ofthe titled compound as a brown oily matter.

IR(neat): 3302, 2902, 2846, 2279, 2244 cm⁻¹

[B] Preparation of the Present Compounds EXAMPLE 11-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-1)

1,1′-Carbonyldiimidazole (427 mg, 2.63 mmol) was added to a solution of4-(3-aminopropyl)pyridine (Intermediate No. 2-1) (285 mg, 2.09 mmol) intetrahydrofuran (10 ml), and the mixture was stirred at room temperaturefor 20 minutes. 2-(1-Adamantyl)-N-pentylethylamine hydrochloride(Intermediate No. 1-1) (571 mg, 2.00 mmol) was added to the mixture, andthe whole was refluxed for one hour. The reaction mixture was dilutedwith ethyl acetate (50 ml), the whole was washed with a saturatedaqueous sodium hydrogencarbonate solution (50 ml) and a saturatedaqueous sodium chloride solution (50 ml) successively, and the organiclayer was dried over magnesium sulfate. The solvent was evaporated underreduced pressure, and the precipitated solid was washed with diisopropylether and filtered off to give 606 mg (73%) of the titled compound.

IR(KBr): 2900, 2845, 1618, 1534 cm⁻¹

mp: 124.0-124.7° C.

The following compounds were obtained by a method similar to Example 1.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea(Compound No. 1-2)

IR(neat): 3339, 2902, 2846, 1626, 1530 cm⁻¹

N-[3-(4-Pyridyl)propyl]-1-piperidinecarboxamide (Compound No. 1-3)

IR(neat): 3339, 2934, 2854, 1621, 1538 cm⁻¹

N-[3-(4-Pyridyl)propyl]-1,2,3,6-tetrahydropyridine-1-carboxamide(Compound No. 1-4)

IR(neat): 3337, 2922, 2858, 1624, 1537, 1414 cm⁻¹

N-[3-(4-Pyridyl)propyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide(Compound No. 1-5)

IR(KBr): 3342, 2925, 1614, 1543, 1489 cm⁻¹

mp: 76.0-79.0° C.

N-[3-(4-Pyridyl)propyl]-4-morpholinecarboxamide (Compound No. 1-6)

IR(KBr): 3347, 2968, 1626, 1546, 1115 cm⁻¹

mp: 94.0-98.0° C.

N-[3-(4-Pyridyl)propyl]-1-homopiperidinecarboxamide (Compound No. 1-7)

IR(neat): 3343, 2927, 1625, 1537 cm⁻¹

1,1-Diallyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-8)

IR(neat): 3350, 2928, 1628, 1603, 1535 cm⁻¹

N-[3-(4-Pyridyl)propyl]-2-decahydroisoquinolinecarboxamide (Compound No.1-9)

IR(neat): 3343, 2855, 2622, 1621, 1539 cm⁻¹

1,1-Dibutyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-10)

IR(neat): 3347, 2957, 2872, 1626, 1537 cm⁻¹

1,1-Dihexyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-11)

IR(neat): 3348, 2928, 2857, 1626, 1532 cm⁻¹

1,1-Diisopentyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-12)

IR(neat): 3344, 29.55, 2869, 1626, 1533 cm⁻¹

1,1-Didecyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-13)

IR(neat): 3346, 2925, 2854, 1626, 1537 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-14)

IR(neat): 3360, 2902, 2846, 1772, 1699, 1634, 1532 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-(dimethylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-15)

IR(KBr): 3322, 2900, 2845, 1621, 1526 cm⁻¹

mp: 104.0-106.5° C.

1-[2-(1-Adamantyl)ethyl]-1-propyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-16)

IR(KBr): 3331, 2901, 2846, 1622, 1602, 1534 cm⁻¹

mp: 99.0-103.0° C.

1-[2-(1-Adamantyl)ethyl]-1-(2-propynyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-17)

IR(KBr): 3322, 3204, 2899, 2845, 2112, 1626, 1605, 1543, 1444 cm⁻¹

mp: 152.0-154.0° C.

1-[2-(1-Adamantyl)ethyl]-1-(2-methoxyethyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-18)

IR(KBr): 3321, 2900, 2846, 1625, 1602, 1534, 1451 cm⁻¹

mp: 101.5-104.5° C.

1-[2-(1-Adamantyl)ethyl]-1-cyclopropyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-19)

IR(KBr): 3365, 2900, 1633 cm⁻¹

mp: 108.0-115.5° C.

1-[2-(1-Adamantyl)ethyl]-1-cyanomethyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-20)

IR(neat): 3350, 2903, 2247, 1644 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-cyclopentylmethyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-21)

IR(KBr): 3328, 2906, 2845, 1615, 1450 cm⁻¹

mp: 155.0-158.0° C.

1-[2-(1-Adamantyl)ethyl]-1-cyclopropylmethyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-22)

IR(KBr): 3328, 2900, 2845, 1618, 1534 cm⁻¹

mp: 123.0-125.0° C.

1-[2-(1-Adamantyl)ethyl]-1-allyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-23)

IR(KBr): 3329, 2900, 1625, 1538 cm⁻¹

mp: 99.0-102.0° C.

1-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]-1-(3,3,3-trifluoropropyl)urea(Compound No. 1-24)

IR(KBr): 3310, 2900, 2847, 1622, 1543 cm⁻¹

mp: 107.5-109.0° C.

1-[2-(1-Adamantyl)ethyl]-1-(2-butenyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-25)

IR(KBr): 3328, 2900, 1619 cm⁻¹

mp: 89.5-93.5° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-26)

IR(neat): 3350, 2903, 2846, 1694, 1633, 1537 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]-1-(2-thienyl)methylurea(Compound No. 1-27)

IR(KBr): 3328, 2900, 2845, 1626, 1544 cm⁻¹

mp: 142.5-144.5° C.

1-[2-(1-Adamantyl)ethyl]-1-benzyloxy-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-28)

IR(neat): 3444, 3350, 2902, 2846, 1666, 1517 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-hexyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-29)

IR(KBr): 3354, 2901, 2845, 1619, 1538 cm⁻¹

mp: 119.5-121.5° C.

1-(1-Adamantyl)methyl-1-propyl-3-[3-(4-pyridyl)propyl]urea (Compound No.1-30)

IR(neat): 3350, 2902, 1626 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-(3-methyl-2-butenyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-31)

IR(KBr): 3358, 2900, 2845, 1622, 1526 cm⁻¹

mp: 93.0-96.0° C.

1-[2-(1-Adamantyl)ethyl]-1-decyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-32)

IR(KBr): 3340, 2924, 2846, 1626, 1602, 1534 cm⁻¹

mp: 75.0.-76.0° C.

1-[2-(1-Adamantyl)ethyl]-1-(2-methyl-2-propenyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-33)

IR(KBr): 3336, 2905, 2846, 1624, 1544 cm⁻¹

mp: 108.0-109.0° C.

1-[2-(1-Adamantyl)ethyl]-1-cinnamyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-34)

IR(KBr): 3374, 2899, 2844, 1619, 1534 cm⁻¹

mp: 130.0-134.5° C.

1-[3-(1-Adamantyl)propyl]-1-propyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-35)

IR(neat): 3349, 2901, 1626, 1536 cm⁻¹

1-(1-Adamantyl)methyl-1-pentyl-3-[3-(4-pyridyl)propyl]urea (Compound No.1-36)

IR(neat): 3349, 2903, 1625, 1531 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-(2-methylthiazol-4-yl)methyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-37)

IR(neat): 3337, 2901, 1632, 1536 cm⁻¹

1,1-Dipentyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-38)

IR(neat): 3347, 2929, 2859, 1626, 1537 cm⁻¹

1-Pentyl-1-(2-piperidinoethyl)-3-[3-(4-pyridyl)propyl]urea (Compound No.1-39)

IR(neat): 3350, 2933, 2856, 1640, 1533 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-methyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-40)

IR(KBr): 3334, 2901, 2846, 1626, 1604, 1534 cm⁻¹

mp: 99.0-109.0° C.

1-[2-(1-Adamantyl)ethyl]-1-ethyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-41)

IR(KBr): 3324, 2901, 2845, 1622, 1540 cm⁻¹

mp: 106.0-115.0° C.

1-[2-(1-Adamantyl)ethyl]-1-furfuryl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-42)

IR(KBr): 3331, 2900, 2846, 1618, 1538 cm⁻¹

mp: 128.0-130.0° C.

1-[2-(1-Adamantyl)ethyl]-1-benzyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-43)

IR(KBr): 3335, 2901, 2847, 1619, 1538 cm⁻¹

mp: 130.5-135.0° C.

1-(2-Cyclohexylethyl)-1-pentyl-3-[3-(4-pyridyl)propyl]urea (Compound No.1-44)

IR(neat): 3345, 2923, 1625, 1603, 1531 cm⁻¹

1-Pentyl-1-phenethyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-45)

IR(neat): 3345, 3063, 2929, 1625, 1533 cm⁻¹

1-Butyl-1-(2-cyclohexylethyl)-3-(4-pyridyl)methylurea (Compound No.1-46)

IR(neat): 3342, 2922, 2851, 1629, 1602, 1563, 1530, 1448 cm⁻¹

1-(2-Cyclohexylethyl)-1,3-bis[(4-pyridyl)methyl]urea (Compound No. 1-47)

IR(neat): 3337, 3029, 2922, 2850, 1633, 1602, 1534, 1445 cm⁻¹

1-(2-Cyclohexylethyl)-3-(4-pyridyl)methyl-1-(2-thienyl)methylurea(Compound No. 1-48)

IR(neat): 3342, 2921, 2850, 1631, 1602, 1562, 1536, 1415, 1267, 1227cm⁻¹

1-[2-(t-Butoxycarbonyl)ethyl]-1-(2-cyclohexylethyl)-3-(4-pyridyl)methylurea(Compound No. 1-49)

IR(neat): 3347, 2977, 2923, 2851, 1727, 1633, 1602, 1563, 1531, 1449cm⁻¹

1-(2-Cyclohexylethyl)-1-[2-(methoxycarbonyl)ethyl]-3-(4-pyridyl)methylurea(Compound No. 1-50)

IR(neat): 3348, 2923, 2850, 1737, 1633, 1603, 1563, 1532, 1437 cm⁻¹

1-(2-Carbamoylethyl)-1-(2-cyclohexylethyl)-3-(4-pyridyl)methylurea(Compound No. 1-51)

IR(neat): 3324, 2922, 2850, 1673, 1632, 1606, 1563, 1530, 1448 cm⁻¹

1-(2-Cyclohexylethyl)-1-pentyl-3-(4-pyridyl)methylurea (Compound No.1-52)

IR(KBr): 3313, 2925, 1627, 1602, 1527, 1410 cm⁻¹

mp: 64.7-65.8° C.

1-(2-Cyclohexylethyl)-1-(2-dimethylaminoethyl)-3-(4-pyridyl)methylurea(Compound No. 1-53)

IR(KBr): 3346, 2922, 2850, 2778, 1635, 1562, 1533, 1448 cm⁻¹

1-[2-[N-(t-Butoxycarbonyl)-N-methylamino]ethyl]-1-(2-cyclohexylethyl)-3-(4-pyridyl)methylurea(Compound No. 1-54)

IR(neat): 3338, 2976, 2924, 2851, 1694, 1633, 1602, 1563, 1531, 1484,1450 cm⁻¹

1-Pentyl-1-[2-(2-pyridyl)ethyl]-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-55)

IR(neat): 3350, 2929, 2859, 1633, 1602, 1537 cm⁻¹

1,1-Bis[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea (Compound No.1-56)

IR(neat): 3358, 2901, 2845, 1625, 1530 cm⁻¹

mp: 80° C.

1-[2-(1-Adamantyl)ethyl]-1-butyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-57)

IR(KBr): 3315, 2901, 1618, 1534 cm⁻¹

mp: 109.5-118.0° C.

1,1-Bis(2-hydroxypropyl)-3-[3-(4-pyridyl)propyl]urea hydrochloride(Compound No. 1-58)

IR(neat): 3350, 1688, 1638, 1538 cm⁻¹

1-[Bis(t-butoxycarbonylaminomethyl)]methyl-1-isopentyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-59)

IR(neat): 3326, 2960, 1698, 1631, 1525 cm⁻¹

1-Cyclohexyl(phenyl)methyl-1-(3-phenylpropyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-60)

IR(KBr): 3352, 2931, 1619, 1522 cm⁻¹

mp: 107.0-112.0° C.

1,1-Dicyclohexyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-61)

IR(KBr): 3304, 2930, 2848, 1638, 1602, 1533 cm⁻¹

mp: 143.0-145.5° C.

1-[2-[N-(t-Butoxycarbonyl)-N-methylamino]ethyl]-1-phenethyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-62)

IR(neat): 3350, 1694, 1633, 1532, 1166 cm⁻¹

1-[2-[N-(t-Butoxycarbonyl)-N-methylamino]ethyl-1-pentyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-63)

IR(neat): 3350, 1694, 1632, 1537, 1167 cm⁻¹

1-[2-(N-Benzyloxycarbonyl-N-methylamino)ethyl]-1-phenethyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-64)

IR(neat): 3350, 1698, 1632, 1531 cm⁻¹

1-[3-(1-Adamantyl)propyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-65)

IR(KBr): 3333, 2901, 2844, 1623, 1602, 1543 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-pentyl-1-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-66)

IR(KBr): 3370, 3322, 2903, 2846, 1618, 1534 cm⁻¹

mp: 47.0-50.0° C.

3-[2-(1-Adamantyl)ethyl]-1-[2-(t-butoxycarbonyl)ethyl]-1-[3-(4-pyridyl)propyl]urea(Compound No. 1-67)

IR(neat): 3348, 2902, 2846, 1726, 1627, 1538, 1367, 1152 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-isopropyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-68)

IR(KBr): 3330, 2903, 2845, 1614, 1533 cm⁻¹

mp: 132.0-134.0° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-(t-butoxycarbonyl)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-69)

IR(KBr): 3356, 2903, 1720, 1622, 1538, 1156 cm⁻¹

mp: 124.5-127.0° C.

1-[2-(1-Adamantyl)ethyl]-1-cyclopentyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-70)

IR(KBr): 3297, 2906, 2844, 1618, 1544 cm⁻¹

mp: 135.5-137.5° C.

1-[2-(1-Adamantyl)ethyl]-1-(t-butoxycarbonylamino)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-71)

IR(neat): 3231, 2903, 1732, 1650 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-(2-pyridyl)methylurea (Compound No.1-72)

IR(KBr): 3333, 2900, 2844, 1625, 1535 cm⁻¹

mp: 87.5-92.0° C.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-(3-pyridyl)methylurea (Compound No.1-73)

IR(KBr): 3328, 2901, 2846, 1622, 1530 cm⁻¹

mp: 88.5-101.5° C.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-(4-pyridyl)methylurea (Compound No.1-74)

IR(KBr): 3331, 2900, 2845, 1626, 1538 cm⁻¹

mp: 96.5-108.0° C.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(2-pyridyl)ethyl]urea (CompoundNo. 1-75)

IR(KBr): 3346, 2904, 2845, 1622, 1539 cm⁻¹

mp: 80.0-100.0° C.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(3-pyridyl)ethyl]urea (CompoundNo. 1-76)

IR(KBr): 3334, 2900, 2845, 1618, 1541 cm⁻¹

mp: 112.5-114.5° C.

1-(2-Cyclohexylethyl)-1-(2-methoxyethyl)-3-(4-pyridyl)methylurea(Compound No. 1-77)

IR(neat): 3350, 2922, 2850, 1633, 1603, 1534 cm⁻¹

1-[2-(N-Benzyloxycarbonyl-N-methylamino)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-78)

IR(neat): 3358, 2930, 1701, 1633, 1534 cm⁻¹

1-Ethyl-3-[3-(4-pyridyl)propyl]-1-(3,4,5-trimethoxyphenethyl)urea(Compound No. 1-79)

IR(neat): 3350, 2936, 1626, 1590, 1530, 1239 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(4-pyridyl)ethyl]urea (CompoundNo. 1-80)

IR(KBr): 3346, 2901, 2844, 1622, 1538 cm⁻¹

mp: 107-118° C.

1-[2-(1H-5-Imidazolyl)ethyl]-1-isopentyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-81)

IR(neat): 3117, 2954, 1606, 15.37 cm⁻¹

1-Cyclohexyl-1-(3,4-dimethoxyphenethyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-82)

IR(neat): 3353, 2931, 1621, 1515, 1236, 1029 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(2-pyridyl)propyl]urea (CompoundNo. 1-83)

IR(KBr): 3324, 2900, 2845, 1622, 1538 cm⁻¹

mp: 84.4-85.7° C.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(3-pyridyl)propyl]urea (CompoundNo. 1-84)

IR(KBr): 3355, 2902, 2845, 1615, 1526 cm⁻¹

mp: 99.9-105.2° C.

1-Cyclopropyl-3-[3-(4-pyridyl)propyl]-1-(3,4,5-trimethoxyphenethyl)urea(Compound No. 1-85)

IR(neat): 3400, 2938, 1644, 1590, 1510, 1239, 1128 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-(4-dimethylamino)phenethyl-1-pentylurea(Compound No. 1-86)

IR(KBr): 3341, 2900, 2845, 1619, 1526 cm⁻¹

mp: 115.8-118.1° C.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[4-(4-pyridyl)butyl]urea (CompoundNo. 1-87)

IR(KBr): 3354, 2900, 2844, 1618, 1538 cm⁻¹

mp: 74.1-78.1° C.

1-[2-(1-Adamantyl)ethyl]-3-(t-butoxycarbonyl)-1-pentyl-3-[2-(4-pyridyl)oxyethyl]urea(Compound No. 1-88)

IR(neat): 2903, 2847, 1704, 1590 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[3-[N-(t-butoxycarbonyl)-N-methylamino]propyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-89)

IR(neat):-3350, 2903, 2847, 1694, 1632, 1531 cm⁻¹

1-Cyclohexyl(phenyl)methyl-1-[3-(4-methoxyphenoxy)propyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-90)

IR(neat): 3369, 2930, 1626, 1510, 1231 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-quinolyl)propyl]urea (CompoundNo. 1-91)

IR(KBr): 3354, 2902, 2845, 1622, 1534 cm⁻¹

mp: 80.2-102.0° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(1-imidazolylcarbonyl)-N-methylamino]ethyl]-3-[3-(4-pyridylpropyl]urea (Compound No. 1-92)

IR(neat): 3366, 2902, 2846, 1695, 1635, 1604, 1531 cm⁻¹

1-Diphenylmethyl-1-(3-phenylpropyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-93)

IR(KBr): 3334, 3026, 2927, 1621, 1522 cm⁻¹

mp: 123.0-124.8° C.

1,1-Di(5-hexenyl)-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-94)

IR(neat): 3350, 3074, 2930, 2859, 1621, 1538 cm⁻¹

1,1-Di(7-octenyl)-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-95)

IR(neat): 3349, 3074, 2927, 2856, 1625, 1537 cm⁻¹

4-[2-[3-[2-(1-Adamantyl)ethyl]-3-pentyl]ureidoethyl]benzenesulfonamide(Compound No. 1-96)

IR(KBr): 3423, 2906, 2847, 1598, 1540, 1161 cm⁻¹

mp: 85.0-120.7° C.

1-[2-(1-Adamantyl)ethyl]-3-(1-imidazolyl)propyl-1-pentylurea (CompoundNo. 1-97)

IR(KBr): 3340, 2902, 2845, 1618, 1534 cm⁻¹

mp: 97.0-100.0° C.

1-[2-(1-Adamantyl)ethyl]-3-(4-hydroxyphenethyl)-1-pentylurea (CompoundNo. 1-98)

IR(KBr): 3392, 2902, 2845, 1614, 1535, 1515 cm⁻¹

mp: 96.3-99.4° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-(3-t-butyl-1-methylureido)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-99)

IR(neat): 3310, 2903, 1632, 1537 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-100)

IR(KBr): 3347, 2957, 2902, 2846, 1621, 1604, 1539 cm⁻¹

mp: 105.3-112.3° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-(1-methyl-3-propylureido)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-101)

IR(neat): 3316, 2902, 1631, 1537 cm⁻¹

1-Pentyl-1-(3-phenylpropyl)-3-[3-(4-pyridyl)propyl]urea (Compound No.1-102)

IR(neat): 3348, 2929, 1625, 1537 cm⁻¹

1-[2-(Acetylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-103)

IR(neat): 3291, 2902, 2846, 1632, 1556, 753 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)butyl]urea (CompoundNo. 1-104)

IR(KBr): 3346, 2901, 2845, 1618, 1601, 1539 cm⁻¹

mp: 93.0-98.0° C.

1-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]-1-(4,4,4-trifluorobutyl)urea(Compound No. 1-105)

IR(KBr): 3317, 2901, 2846, 1618, 1538, 1255, 1123 cm⁻¹

mp: 142.6-145.0° C.

1-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]-1-(5,5,5-trifluoropentyl)urea(Compound No. 1-106)

IR(KBr): 3333, 2900, 2846, 1618, 1534, 1259, 1140 cm⁻¹

mp: 116.9-118.9° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]urea(Compound No. 1-107)

IR(neat): 3350, 2902, 2846, 1694, 1672, 1633, 1603, 1537 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(4-pyridylmethyl)butyl]urea(Compound No. 1-108)

IR(KBr): 3347, 2900, 2845, 1622, 1538 cm⁻¹

mp: 72.0-77.0° C.

1-[2-(1-Adamantyl)ethyl]-3-[2-benzyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-109)

IR(KBr): 3329, 2902, 2846, 1622, 1544 cm⁻¹

mp: 111.0-116.0° C.

1-[2-(1-Adamantyl)ethyl]-3-[2,2-bis(4-pyridylmethyl)ethyl]-1-pentylurea(Compound No. 1-110)

IR(KBr): 3330, 2905, 2845, 1619, 1602, 1534 cm⁻¹

mp:124.0-136.0° C.

(Z)-1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea(Compound No. 1-111)

IR(neat): 3338, 2901, 2846, 1625, 1596, 1530 cm⁻¹

(E)-1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea(Compound No. 1-112)

IR(KBr): 3315, 2900, 2845, 1623, 1526 cm⁻¹

mp: 90-118° C.

1-Isopentyl-3-[3-(4-pyridyl)propyl]-1-(3,3,3-trifluoropropyl)urea(Compound No. 1-113)

IR(neat): 3342, 2956, 1628, 1604, 1539 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]-1-(2,2,2-trifluoroethyl)urea(Compound No. 1-114)

IR(KBr): 3346, 2901, 2847, 1630, 1604, 1544, 1145, 1108 cm⁻¹

mp: 106.2-107.3° C.

3-[2-Methyl-3-(4-pyridyl)propyl]-1-pentyl-1-phenethylurea (Compound No.1-115)

IR(KBr): 3352, 2927, 2858, 1622, 1530, 1496, 1453, 1416, 1276 cm⁻¹

mp: 49.0-50.0° C.

1,1-Dibutyl-3-[2-methyl-3-(4-pyridyl)propyl]urea (Compound No. 1-116)

IR(neat): 3347, 2957, 2929, 1624, 1534 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-(3,3,3-trifluoropropyl)urea(Compound No. 1-117)

IR(KBr): 3354, 2901, 2847, 1626, 1540 cm⁻¹

mp: 81.1-84.1° C.

1-(2-Cyclohexylethyl)-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-118)

IR(neat): 3346, 2923, 2852, 1625, 1533 cm⁻¹

1-(3-Cyclohexylpropyl)-1-propyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-119)

IR(neat): 3346, 2922, 1626, 1537 cm⁻¹

(−)-1-[2-(1-Adamantyl)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-120)

IR(KBr): 3337, 2900, 1616, 1526 cm⁻¹

mp: 103.0-104.0° C.

[α]²⁰ _(D): −4.6° (MeOH, C 1.0)

(+)-1-[2-(1-Adamantyl)ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-121)

IR(KBr): 3336, 2900, 1616, 1526 cm⁻¹

mp: 102.9-103.5° C.

[α]²⁰ _(D): +4.20 (MeOH, C 1.0)

1-[3-(1-Adamantyl)propyl]-1-butyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-122)

IR(KBr): 3323, 2954, 2904, 2846, 1624, 1603, 1548 cm⁻¹

mp: 79.8-80.4° C.

1-[3-(1-Adamantyl)propyl)-3-[3-(4-pyridyl)propyl]-1-(2,2,2-trifluoroethyl)urea(Compound No. 1-123)

IR(KBr): 3355, 2902, 2848, 1627, 1605, 1545, 1145, 1112 cm⁻¹

mp: 88.9-90.0° C.

1-[4-(1-Adamantyl)butyl]-1-ethyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-124)

IR(KBr): 3352, 2897, 2847, 1626, 1604, 1539 cm⁻¹

mp: 92.7-93.7° C.

1-[4-(1-Adamantyl)butyl]-1-propyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-125)

IR(KBr): 3343, 2900, 2847, 1625, 1604, 1544 cm⁻¹

mp: 110.0-110.5° C.

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(4-pyrildylamino)ethyl]urea(Compound No. 1-126)

IR(KBr): 3301, 2904, 2848, 11628, 1602, 1527 cm⁻¹

mp: 133.9-134.5° C.

(+)-1-[3-(1-Adamantyl)propyl]-3-[2-methyl-3-(4-pyridyl)propyl]-1-propylurea(Compound No. 1-127)

IR(neat): 3350, 2902, 2846, 1625, 1534 cm⁻¹

[α]²⁰ _(D): +4.2° (MeOH, C 0.51)

1-[3-(1-Adamantyl)propyl]-1-propyl-3-(4-pyridyl)methylurea (Compound No.1-128)

IR(KBr): 3319, 2902, 1630, 1604, 1537 cm⁻¹

mp: 96.0-98.0° C.

1-[3-(1-Adamantyl)propyl]-1-propyl-3-[2-(4-pyridyl)ethyl]urea (CompoundNo. 1-129)

IR(neat): 3345, 2901, 1634, 1538 cm⁻¹

1-[3-(1-Adamantyl)propyl]-1-ethyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-130)

IR(KBr): 3345, 2969, 2905, 2845, 1622, 1605, 1535 cm⁻¹

mp: 97.5-98.2° C.

1-[2-(1-Adamantyloxy)ethyl]-1-propyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-131)

IR(neat): 3344, 2911, 2853, 1642, 1603, 1534 cm⁻¹

1-(1-Adamantyl)aminocarbonylmethyl-1-propyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-132)

IR(KBr): 3335, 3261, 2910, 2853, 1662, 1622, 1543 cm⁻¹

mp: 132.0-132.5° C.

1-[3-(1-Adamantyl)propyl]-1-propyl-3-[4-(4-pyridyl)butyl]urea (CompoundNo. 1-133)

IR(neat): 3350, 2901, 1623, 1532 cm⁻¹

1-[3-(1-Adamantyl)propyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-134)

IR(neat): 3347, 2902, 2846, 1696, 1632, 1603, 1534, 1167 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[2,2-dimethyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-135)

IR(KBr): 3338, 2905, 1620, 1600, 1541 cm⁻¹

mp: 82.5-84.9° C.

1-[3-(1-Adamantyl)propyl]-3-[3-(4-pyridyl)propyl]-1-(3,3,3-trifluoropropyl)urea(Compound No. 1-136)

IR(neat): 3349, 2902, 1628, 1538 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[1-methyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-137)

IR(KBr): 3338, 2902, 2847, 1615, 1533 cm⁻¹

mp: 128.5-129.0° C.

1-[2-(1-Adamantyl)ethyl]-3-[3-(t-butyldimethylsilyloxy)-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-138)

IR(neat): 3355, 2904, 2849, 1628, 1600, 1532, 1099 cm⁻¹

(+)-1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]urea(Compound No. 1-139)

IR(KBr): 3345, 2910, 2848, 1693, 1622, 1602, 1538, 1248 cm⁻¹

mp: 122.7-123.7° C.

[α]²⁰ _(D): +2.80 (MeOH, C 1.0)

1-[2-(1-Adamantyl)aminoethyl]-1-propyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-140)

IR(neat): 3275, 2908, 2849, 1636, 1536 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-(2-butynyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-141)

IR(neat): 3351, 2903, 2847, 2290, 2221, 1630, 1605, 1538 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[1,2-dimethyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-142)

IR(neat): 3354, 2904, 2847, 1623, 1604, 1525 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[1-ethyl-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-143)

IR(neat): 3352, 2904, 2847, 1622, 1605, 1529 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-3-[3-(t-butyldiphenylsilyloxy)-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-144)

IR(neat): 3360, 3072, 3050, 2903, 2849, 1634, 1602, 1532, 1428 cm⁻¹

EXAMPLE 2 5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-propylamide (Compound No. 2-1)

N,N-Dimethylformamide (8.4 ml) was added to a mixture of2-(1-adamantyl)-N-propylethylamine (Intermediate No. 1-6) (0.37 g, 1.7mmol) and 5-(4-pyridyl)valeric acid (Intermediate No. 5-1) (0.30 g, 1.7mmol), and the whole was stirred at room temperature. N-Methylmorpholine(0.27 ml, 2.5 mmol) and then1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2.0mmol) were added thereto, and the whole was stirred overnight. Thereaction mixture was concentrated under reduced pressure, ethyl acetate(20 ml) was added to the residue, and the whole was washed with asaturated aqueous sodium hydrogencarbonate solution (20 ml) andsaturated brine (5 ml) successively. The organic layer was dried oversodium sulfate, and ethyl acetate was evaporated under reduced pressure.The residue was purified by basic silica gel column chromatography togive 0.21 g (33%) of the titled compound as a colorless oily matter.

IR(neat): 2092, 2846, 1644, 1602 cm⁻¹

The following compounds were obtained by a method similar to Example 2.

5-(4-Pyridyl)valeric acid N-(1-adamantyl)methyl-N-propylamide (CompoundNo. 2-2)

IR(neat): 3067, 2903, 2847, 1644, 1602 cm⁻¹

5-(4-Pyridyl)valeric acid N-(1-adamantyl)methyl-N-pentylamide (CompoundNo. 2-3)

IR(neat): 2903, 2847, 1644, 1601, 1454 cm⁻¹

5-(4-Pyridyl)valeric acid N,N-dibutylamide (Compound No. 2-4)

IR(neat): 2958, 2932, 1641, 1602 cm⁻¹

5-(4-Pyridyl)valeric acid N,N-diisopentylamide (Compound No. 2-5)

IR(neat): 2956, 2870, 1639, 1603 cm⁻¹

5-(4-Pyridyl)valeric acid N-[2-(1-adamantyl)ethyl]-N-(2-butenyl)amide(Compound No. 2-6)

IR(neat): 2903, 2847, 1642, 1602 cm⁻¹

5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-[2-[N′-(t-butoxycarbonyl)-N-methylamino]ethyl]amide(Compound No. 2-7)

IR(neat): 2904, 2847, 1695, 1644, 1602 cm⁻¹

5-(4-Pyridyl)valeric acid N-[3-(1-adamantyl)propyl]-1-propylamide(Compound No. 2-8)

IR(neat): 2902, 2846, 1643, 1602 cm⁻¹

5-(4-Pyridyl)valeric acid N-pentyl-N-phenethylamide (Compound No. 2-9)

IR(neat): 2930, 2860, 1642, 1602 cm⁻¹

5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-(2-dimethylaminoethyl)amide (Compound No.2-10)

IR(neat): 2903, 2847, 1639, 1605 cm⁻¹

5-(4-Pyridyl)valeric acid N-(2-cyclohexylethyl)-N-pentylamide (CompoundNo. 2-11)

IR(neat): 2924, 2853, 1644, 1601 cm⁻¹

5-(4-Pyridyl)valeric acid N,N-bis[2-(1-adamantyl)ethyl]amide (CompoundNo. 2-12)

IR(neat): 2901, 2846, 1643, 1602 cm⁻¹

5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-(3,3,3-trifluoropropyl)amide (Compound No.2-13)

IR(neat): 2904, 2848, 1647, 1602 cm⁻¹

5-(4-Pyridyl)valeric acid N-[2-(1-adamantyl)ethyl]-N-pentylamide(Compound No. 2-14)

IR(neat): 2903, 2847, 1736, 1643, 1602 cm⁻¹

3-(4-Pyridylmethylthio)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 2-15)

IR(neat): 2903, 1643, 1599 cm⁻¹

2-Methyl-3-(4-pyridylmethylthio)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 2-16)

IR(neat): 2903, 1639, 1600 cm⁻¹

2-(t-Butoxycarbonyl)amino-3-(4-pyridylmethylthio)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 2-17)

IR(neat): 3284, 2903, 1705, 1644 cm⁻¹

2-[2-(4-Pyridyl)ethylthio]acetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 2-18)

IR(neat): 2902, 1635, 1602 cm⁻¹

(2R)-2-(t-Butoxycarbonyl)amino-3-[2-(4-pyridyl)ethylthio]propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 2-19)

IR(neat): 3287, 2903, 1705, 1644, 1602 cm⁻¹

[α]²⁰ _(D): −19.0° (MeOH, C 0.43)

6-(4-Pyridyl)caproic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide(Compound No. 2-20)

IR(neat): 2903, 1644, 1602 cm⁻¹

4-(4-Pyridyl)butyric acid N-[2-(1-adamantyl)ethyl]-N-pentylamide(Compound No. 2-21)

IR(neat): 2903, 1644, 1602 cm⁻¹

EXAMPLE 31-[2-(1-Adamantyl)ethyl]-1-(2-methylaminoethyl)-3-[3-(4-pyridyl)propyl]ureadihydrochloride (Compound No. 3-1)

Methanol (4.4 ml) was added to1-[2-(1-adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-26) (0.30 g, 0.6 mmol), a calcium chloride tube wasattached to the vessel, and the mixture was stirred at room temperature.A 10% solution of hydrogen chloride in methanol (4.4 ml) was added tothe mixture, the whole was stirred for one day, and the reaction mixturewas concentrated under reduced pressure to give 0.30 g (quantitatively)of the titled compound as pale yellow noncrystalline powder.

IR(neat): 3351, 2904, 2846, 1634, 1538 cm⁻¹

The following compounds were obtained by a method similar to Example 3.

1-(2-Cyclohexylethyl)-1-(2-methylaminoethyl)-3-(4-pyridyl)methylureadihydrochloride (Compound No. 3-2)

IR(neat): 3323, 2923, 2850, 1638, 1529, 1449 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-amino-3-[3-(4-pyridyl)propyl]ureadihydrochloride (Compound No. 3-3)

IR(KBr): 3410, 2902, 1637 cm⁻¹

mp: about 100° C.

2-Amino-3-(4-pyridylmethylthio)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide dihydrochloride (Compound No.3-4)

IR(neat): 3402, 2901, 1638, 1608, 1503 cm⁻¹

5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-(2-methylaminoethyl)amide (Compound No. 3-5)

IR(neat): 3312, 2902, 2846, 1643, 1602, 1450, 1416 cm⁻¹

(2R)-2-Amino-3-[2-(4-pyridyl)ethylthio]propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide dihydrochloride (Compound No.3-6)

IR(KBr): 3423, 2902, 1638, 1609 cm⁻¹

[α]²⁰ _(D): −4.9° (H₂O, C 0.52)

1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(4-pyridyl)oxyethyl]urea(Compound No. 3-7)

IR(neat): 3246, 2903, 2846, 1698, 1604 cm⁻¹

EXAMPLE 44-[3-[3-[2-(1-Adamantyl)ethyl]-3-pentylureido]propyl]-1-methylpyridiniumiodide (Compound No. 4-1)

Methyl iodide (90 μl, 1.5 mmol) was added to a solution of1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-1) (0.30 g, 0.73 mmol) in acetone (1.5 ml) at room temperature,and the mixture was stirred overnight. The solvent was evaporated underreduced pressure from the reaction mixture, and the precipitatedcrystals were filtered off with ethyl acetate to give 389 mg (96%) ofthe titled compound.

IR(KBr): 3374, 2926, 2900, 1616, 1526 cm⁻¹

mp: 168.0-171.0° C.

The following compounds were obtained by a method similar to Example 4.

4-[3-[3-[2-(1-Adamantyl)ethyl]-3-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]ureido]propyl]-1-methylpyridiniumiodide (Compound No. 4-2)

IR(neat): 3342, 2903, 2846, 1682, 1644, 1520, 1235, 1166 cm⁻¹

4-[3-[3-[2-(1-Adamantyl)ethyl]-3-[2-[N-(t-butoxycarbonyl)amino]ethyl]ureido]propyl]-1-benzylpyridiniumbromide (Compound No. 4-3)

IR(KBr): 3312, 2907, 2846, 1714, 1694, 1625, 1534, 1246, 1171 cm⁻¹

mp: 97° C.

EXAMPLE 5 3-(4-Pyridyl)propyl N-[2-(1-adamantyl)ethyl]-N-pentylcarbamate(Compound No. 5-1)

4-Pyridinepropanol (528 mg, 3.85 mmol) was dissolved in acetonitrile (20ml) at room temperature, and then triethylamine (1.61 ml, 11.6 mmol) wasadded to the solution. Further, N,N′-disuccinimidyl carbonate (1.48 g,5.87 mmol) was added to the mixture, and the whole was stirred for 2.5hours. The reaction mixture was concentrated under reduced pressure, andethyl acetate (100 ml) and a saturated aqueous sodium hydrogencarbonatesolution (50 ml) were added to the residue. Layers were separated, andthe obtained organic layer was washed with a saturated aqueous sodiumchloride solution (50 ml). The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was dried under reduced pressure and dissolved in anhydrousmethylene chloride (10 ml). Then, a solution of2-(1-adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1)(1.32 g, 4.62 mmol) and-triethylamine (0.80 ml, 5.7 mmol) in methylenechloride (90 ml) was added thereto, and the mixture was stirred for 1.5hours. The reaction mixture was washed with a saturated aqueous sodiumhydrogencarbonate solution (560 ml) and a saturated aqueous sodiumchloride solution (50 ml) successively, and the organic layer was driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give 1.54 g (97%) of the titled compound as an oilymatter.

IR(neat): 2903, 2847, 1742, 1698 cm⁻¹

The following compounds were obtained by a method similar to Example 5.

1-[2-(1-Adamantyl)ethyl]-1-[2-(N-cyclohexyloxycarbonyl-N-methylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 5-2)

IR(neat): 3350, 2904, 2847, 1682, 1633, 1604, 1531 cm⁻¹

3-(4-Pyridyl)propyl N-[3-(1-adamantyl)propyl]-N-propylcarbamate(Compound No. 5-3)

IR(neat): 2901, 2846, 1740, 1695, 1645, 1602, 1461, 1423 cm⁻¹

3-(4-Pyridyl)propylN-[2-(1-adamantyl)ethyl]-N-(3,3,3-trifluoropropyl)carbamate (CompoundNo. 5-4)

IR(neat): 2903, 2847, 1705, 1603, 1482, 1451, 1425 cm⁻¹

3-(4-Pyridyl)propylN-[2-(1-adamantyl)ethyl]-N-[2-[N′-(t-butoxycarbonyl)-N′-methylamino]ethyl]carbamate(Compound No. 5-5)

IR(neat): 2903, 2847, 1699, 1603, 1480, 1424 cm⁻¹

2-Methyl-3-(4-pyridyl)propyl N9-[2-(1-adamantyl)ethyl]-N-pentylcarbamate(Compound No. 5-5)

IR(neat): 2904, 2847, 1701, 1602, 1450, 1424, 1381 cm⁻¹

EXAMPLE 61-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]hexahydro-2,4-pyrimidinedionehydrochloride (Compound No. 6-1)

A 4 N solution of hydrogen chloride in 1,4-dioxane (2.5 ml) was added to1-[2-(1-adamantyl)ethyl]-1-[2-(t-butoxycarbonyl)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-69) (0.23 g, 0.49 mmol), and the mixture was stirred atroom temperature overnight. The reaction mixture was concentrated underreduced pressure, a 1 N aqueous sodium hydroxide solution (20 ml) andethyl acetate (30 ml) were added to the residue, and layers wereseparated. The ethyl acetate layer was washed with water (20 ml) and asaturated aqueous sodium chloride solution (20 ml) successively anddried over anhydrous magnesium sulfate. The ethyl acetate layer wasconcentrated under reduced pressure, and the resulting oily matter wasdissolved in diethyl ether (20 ml). A 4 N solution of hydrogen chloridein ethyl acetate (0.50 ml, 2.00 mol) was added thereto underice-cooling, the mixture was concentrated under reduced pressure, andthe precipitated solid was filtered off with ethyl acetate to give 0.17g (79%) of the titled compound.

IR(KBr): 2902, 2437, 1710, 1666 cm⁻¹

mp: 177.0-178.5° C.

The following compounds were obtained by a method similar to Example 6.

1-[2-(Cyclohexyl)ethyl]-3-(4-pyridyl)methylhexahydro-2,4-pyrimidinedionehydrochloride (Compound No. 6-2)

IR(KBr): 2925, 2850, 1718, 1671, 1600, 1493, 1450 cm⁻¹

mp: 64.0-74.5° C.

3-[2-(1-Adamantyl)ethyl]-1-[3-(4-pyridyl)propyl]hexahydro-2,4-pyrimidinedionehydrochloride (Compound No. 6-3)

IR(KBr): 2906, 2845, 1716, 1696, 1658, 1486 cm⁻¹

mp: 170° C.

EXAMPLE 71-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]thiourea(Compound No. 7-1)

A solution of 4-(3-aminopropyl)pyridine (Intermediate No. 2-1) (0.24 g,1.8 mmol) in anhydrous tetrahydrofuran (10 ml) was added to1,1′-thiocarbonyldiimidazole (0.31 g, 1.8 mmol) under a nitrogenatmosphere, and the mixture was stirred at room temperature. After onehour, a solution of 2-(1-adamantyl)-N-pentylethylamine hydrochloride(Intermediate No. 1-1) (0.50 g, 1.8 mmol) in anhydrous tetrahydrofuran(10 ml) was added to the mixture, and the whole was refluxed for 2.5hours. The reaction mixture was allowed to stand, then ethyl acetate (50ml) and a saturated aqueous sodium hydrogencarbonate solution (50 ml)were added to the reaction mixture, and layers were separated. The ethylacetate layer was washed with a saturated aqueous sodium chloridesolution (50 ml) and dried over anhydrous magnesium sulfate. The ethylacetate layer was concentrated under reduced pressure, and theconcentrate was purified by silica gel column chromatography to give0.18 g (24%) of the titled compound.

IR(neat): 3304, 2902, 2846, 1603, 1530, 1345 cm⁻¹

The following compound was obtained by a method similar to Example 7.

1-(2-Hydroxyethyl)-1-phenethyl-3-[3-(4-pyridyl)propyl]thiourea (CompoundNo. 7-2)

IR(KBr): 3022, 2920, 2876, 1606, 1585 cm⁻¹

mp: 105.6-107.1° C.

EXAMPLE 8 1-Phenethyl-3-[3-(4-pyridyl)propyl]-2-imidazolidinethione(Compound No. 8-1)

Anhydrous tetrahydrofuran (2.5 ml) was added to a mixture of1-(2-hydroxyethyl)-1-phenethyl-3-[3-(4-pyridyl)propyl]thiourea (CompoundNo. 7-2) (601 mg, 1.75 mmol) and triphenylphosphine (913 mg, 3.49 mmol),and the whole was stirred under ice/methanol-cooling. A solution ofdiisopropyl azodicarboxylate (710 mg, 3.49 mmol) in anhydroustetrahydrofuran was added dropwise thereto, and after 10 minutes, ethylacetate (100 ml) was added to the reaction mixture. The whole was washedwith a saturated aqueous sodium hydrogencarbonate solution (40 ml) andsaturated brine (40 ml) successively, and the organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography, and the obtained solidwas filtered off with hexane to give 107 mg (19%) of the titled compoundas crystals.

IR(KBr): 3064, 3018, 2926, 2858, 1601, 1560, 1498, 1456 cm⁻¹

mp: 99.5-104.0° C.

EXAMPLE 91-[2-(1-Adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]hexahydropyrimidin-2-one(Compound No. 9-1)

To a solution of 1-adamantaneacetic acid (1.50 g, 7.72 mmol) inanhydrous methylene chloride (310.0 ml) were added1-hydroxybenzotriazole (1.15 g, 8.49 mmol), β-alanine ethyl esterhydrochloride (1.30 g, 8.49 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.63 g,8.49 mmol) and N-methylmorpholine (2.05 ml, 18.7 mmol) underice-cooling, and the mixture was stirred at room-temperature overnight.The reaction mixture was concentrated under reduced pressure, and ethylacetate (50 ml) was added to the residue. The whole was washed with a10% aqueous citric acid solution (50 ml), water (50 ml), a saturatedaqueous sodium hydrogencarbonate solution (50 ml), water (50 ml) and asaturated aqueous sodium chloride solution (50 ml) successively, and theorganic layer was dried over anhydrous magnesium sulfate. The organiclayer was concentrated under reduced pressure to give 2.48 g(quantitatively) of ethyl 3-[(1-adamantly)methylcarboxamido]propionateas a white solid.

Next, ethyl 3-[(1-adamantly)methylcarboxamido]propionate (2.40 g, 8.18mmol) was dissolved in ethanol (5 ml), a 2 N aqueous sodium hydroxidesolution (4.50 ml, 9.00 mmol) was added thereto under ice-cooling, andthe mixture was stirred at room temperature for two hours. Underice-cooling, 2 N hydrochloric acid (15 ml) was added to the reactionmixture to acidify it weakly, and the whole was extracted with ethylacetate (70 ml). The organic layer was washed with water (50 ml) and asaturated aqueous sodium chloride solution (50 ml) successively anddried over anhydrous magnesium sulfate. The organic layer wasconcentrated under reduced pressure, and the precipitated solid wasfiltered off with diethyl ether to give 1.43 g (70.1%) of3-[(1-adamantyl)methylcarboxamido]propionic acid.

Next, to a solution of 3-[(1-adamantyl)methylcarboxamido]propionic acid(1.4 g, 5.6 mmol) in anhydrous methylene chloride (10 my) were added1-hydroxybenzotriazole (0.83 g, 6.2 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 g, 6.2mmol), 4-(3-aminopropyl)pyridine (Intermediate No. 2-1) (0.80 g, 5.9mmol) and N-methylmorpholine (0.68 ml, 6.2 mmol) under ice-cooling, andthe mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, and ethyl acetate (60ml) was added to the residue. The whole was washed with a saturatedaqueous sodium hydrogencarbonate solution (30 ml), water (30 ml) and asaturated aqueous sodium chloride solution (30 ml) successively, and theorganic layer was dried over anhydrous magnesium sulfate. The organiclayer was concentrated under reduced pressure, and the precipitatedsolid was filtered off with diethyl ether to give 1.9 g (88%) of3-[(1-adamantyl)methylcarboxamido]propionic acid3-(4-pyridyl)propylamide.

Anhydrous diethyl ether (20 ml) was added to lithium aluminum hydride(0.45 g, 12 mmol) under ice-cooling. Then, a solution of the obtained3-[(1-adamantyl)methylcarboxamido]propionic acid3-(4-pyridyl)propylamide (0.50 g, 1.3 mmol) in anhydrous tetrahydrofuran(10 ml) was added dropwise to the mixture over 15 minutes, and the wholewas stirred at room temperature overnight and further refluxed for 4.5hours. Then, a 2 N aqueous sodium hydroxide solution (30 ml) and ethylacetate (30 ml) were added carefully to the reaction mixture underice-cooling, and layers were separated. The ethyl acetate layer waswashed with water (30 ml) and a saturated aqueous sodium chloridesolution (30 ml) successively and dried over anhydrous magnesiumsulfate. The ethyl acetate layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give 0.05. g (10%) ofN-[2-(1-adamantyl)ethyl]-N′-[3-(4-pyridyl)propyl]-1,3-propanediamine.

To anhydrous methylene chloride (50 ml) were added a solution of theobtained,N-[2-(1-adamantyl)ethyl]-N′-[3-(4-pyridyl)propyl]-1,3-propanediamine (80mg, 0.23 mmol) in anhydrous methylene chloride (10 ml) and a solution of1,1′-carbonyldiimidazole (40 mg, 0.26 mmol) in anhydrous methylenechloride (10 ml) dropwise simultaneously with stirring at roomtemperature over 20 minutes. The mixture was stirred overnight, thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to give 8.0 mg(9.4%) of the titled compound.

IR(neat): 3400, 2902, 2846, 1625, 1531, 1451 cm⁻¹

EXAMPLE 101-Acetylamino-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-1)

Pyridine (2.0 ml) and acetic anhydride (1.0 ml) were added to1-[2-(1-adamantyl)ethyl]-1-amino-3-[3-(4-pyridyl)propyl]ureadihydrochloride (Compound No. 3-3) (0.20 g, 0.47 mmol) at roomtemperature, and the mixture was stirred for 15 minutes. The solvent wasevaporated under reduced pressure from the reaction mixture, and theresidue was distributed with ethyl acetate (10 ml) and water (10 ml).The organic layer was washed with a saturated aqueous sodiumhydrogencarbonate solution (10 ml) and saturated brine (10 ml) and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give 0.11 g (58%) of the titled compound.

IR(KBr): 3374, 3163, 2907, 1694, 1638 cm⁻¹

mp: 140.0-146.0° C.

The following compounds were obtained by a method similar to Example 10.Acid chlorides were optionally used.

1-[2-(N-Acetyl-N-methylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-2)

IR(neat): 3337, 2902, 1632, 1535, 1492 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-(N-isonicotinoyl-N-methylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-3)

IR(neat): 3350, 2902, 2846, 1633, 1531, 1450, 1408 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-methyl-N-(methylsulfonyl)amino]ethyl]-3-[3-(4-pyridyl)propyl)urea(Compound No. 10-4)

IR(KBr): 3319, 2902, 2845, 1616, 1540, 1326, 1142 cm⁻¹

mp: 164.9-167.2° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-methyl-N-(p-tolylsulfonyl)amino]ethyl]-3-[3(4-pyridyl)propyl]urea (Compound No. 10-5)

IR(neat): 3358, 2902, 2846, 1633, 1603, 1531, 1343, 1161 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(3,3-dimethylbutyryl)-N-methylamino]ethyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-6)

IR(KBr): 3325, 2906, 2845, 1652, 1616, 1534 cm⁻¹

mp: 101.4-102.4° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-(N-ethoxycarbonyl-N-methylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-7)

IR(neat): 3350, 2902, 2846, 1698, 1633, 1532 cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)amino]ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-8)

IR(KBr): 3312, 2905, 2845, 1710, 1637, 1606, 1534, 1269, 1249, 1174 cm⁻¹

mp: 158.0-160.5° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-ethylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-9)

IR(neat): 3349, 2902, 2846, 1693, 1667, 1633, 1603, 1531, 1452, 1416cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(1,1-dimethyl-2,2,2-trichloroethoxycarbonyl)-N-methylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-10)

IR(neat): 3359, 2903, 2846, 1707, 1636, 1603, 1534 cm⁻¹

mp: 47.0-52.0° C.

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(1,1-dimethylpropoxycarbonyl)-N-methylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-11)

IR(neat): 3349, 2972, 2902, 2846, 1695, 1631, 1603, 1534, 1226, 1159cm⁻¹

1-[2-(1-Adamantyl)ethyl]-1-[2-(N-isopropoxycarbonyl-N-methylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-12)

IR(neat): 3350, 2903, 2846, 1696, 1632, 1603, 1530 cm⁻¹

(−)-1-[2-(1-Adamantyl)ethyl]-1-[2-(N-menthoxycarbonyl-N-methylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 10-13)

IR(neat): 3350, 2904, 2847, 1694, 1633, 1603, 1530 cm⁻¹

[α]²⁰ _(D): −27.50 (MeOH, C 1.0)

1-[2-(1-Adamantyl)ethyl]-1-[2-[N-(3,3-dimethylbutyryl)-N-methylamino]ethyl]-3-[2-methyl-3-(4-pyridyl)propyl]urea(Compound No. 10-14)

IR(neat): 3324, 2902, 2846, 1633, 1537 cm⁻¹

5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-[2-(N′-isopropoxycarbonyl-N′-methylamino)ethyl]amide(Compound No. 10-15)

IR(neat): 3553, 2978, 2903, 2847, 1697, 1646 cm⁻¹

5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-[2-(N′-benzyloxycarbonyl-N′-methylamino)ethyl]amide(Compound No. 10-16)

IR(neat): 3387, 3030, 2903, 2847, 1701, 1646, 1602, 1453, 1422 cm⁻¹

5-(4-Pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-[2-[N′-(3,3-dimethylbutyryl)-N′-methylamino]ethyl]amide(Compound No. 10-17)

IR(neat): 3501, 2903, 2847, 1645, 1663, 1455, 1417 cm⁻¹

EXAMPLE 111-[2-(1-Adamantyl)ethyl]-1,3-dimethyl-3-[3-(4-pyridyl)propyl]urea(Compound No. 11-1)

A solution of triphosgene (190 mg, 0.640 mmol) in dichloromethane (6.0ml) was stirred at room temperature under a nitrogen atmosphere. Asolution of 2-(1-adamantyl)-N-methylethylamine (Intermediate No. 3-1)(330 mg, 1.71 mmol) and diisopropylethylamine (0.357 ml, 2.05 mmol) indichloromethane (6.0 ml) was added dropwise thereto over 17 minutes.After eight minutes, a solution of N-methyl-3-(4-pyridyl)propylamine(Intermediate No. 3-3) (264 mg, 1.78 mmol) and diisopropylethylamine.(0.357 ml, 2.05 mmol) in dichloromethane (5.1 ml) was added to themixture at a stretch, and the whole was stirred for 20 hours. The,reaction mixture was diluted with diethyl ether (40 ml), the whole waswashed with a saturated aqueous sodium hydrogencarbonate solution (40ml) twice and a saturated aqueous sodium chloride solution (40 ml)successively, and the organic layer was dried over magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give 335 mg (54%) of thetitled compound.

IR(neat): 2903, 2846, 1638, 1602, 1492 cm⁻¹

EXAMPLE 121-[2-(1-Adamantyl)ethyl]-1-hydroxy-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 12-1)

2 N Hydrochloric acid (4.0 ml) was added to a solution of1-[2-(1-adamantyl)ethyl]-1-benzyloxy-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-28) (438 mg, 0.978 mmol) in methanol (9.78 ml), and anitrogen gas was bubbled through the mixture. To the mixture was added10% palladium on carbon (43 mg), and the whole was stirred underhydrogen at 1 atm for three days. The palladium on carbon was filteredout, the filtrate was concentrated under reduced pressure, and theconcentrate was diluted with diethyl ether (30 ml). The whole was washedwith a saturated aqueous sodium hydrogencarbonate solution (30 ml) and asaturated aqueous sodium chloride solution (30 ml) successively, and theorganic layer was dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give 119 mg (34%) of the titledcompound.

IR(KBr): 3438, 3152, 2903, 2847, 1650 cm⁻¹

mp: 101.0-102.5° C.

EXAMPLE 13 1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]ureahydrochloride (Compound No. 13-1)

A 4 N solution of hydrogen chloride in ethyl acetate (0.400 ml, 1.60mmol) was added to a solution of1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-1) (200 mg, 0.486 mmol) in chloroform (0.3 ml). The solvent wasevaporated under reduced pressure, and the precipitated solid was washedwith ethyl acetate and filtered off. The obtained crude crystals wererecrystallized from 2-butanone (5.0 ml) to give 94 mg (43%) of thetitled compound.

IR(KBr): 3322, 3050, 2902, 2496, 1621, 1534, 1450 cm⁻¹

mp: 157.0-158.0° C.

The following compounds were obtained by a method similar to Example 13.

1-[2-(1-adamantyl)ethyl]-1-propyl-3-[3-(4-pyridyl)propyl]ureahydrochloride (Compound No. 13-2)

IR(neat): 3338, 2901, 2845, 1620, 1450 cm⁻¹

1-(2-Cyclohexylethyl)-3-(4-pyridyl)methyl-1-(2-thienyl)methylureahydrochloride (Compound No. 13-3)

IR(KBr): 3296, 2923, 1635, 1599, 1518 cm⁻¹

mp: 161.8-164.4° C.

1-[2-(1-Adamantyl)ethyl]-1-butyl-3-[3-(4-pyridyl)propyl]ureahydrochloride (Compound No. 13-4)

IR(neat): 3331, 2901, 2845, 1754, 1636, 1537 cm⁻¹

1,1-Bis[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea hydrochloride(Compound No. 13-5)

IR(KBr): 3289, 2900, 2844, 1637, 1560 cm⁻¹

mp: 120.0-122.5° C.

1-[2-(1-Adamantyl)ethyl]-1-(2-aminoethyl)-3-[3-(4-pyridyl)propyl]ureadihydrochloride (Compound No. 13-6)

IR(neat): 3358, 2902, 2846, 1634, 1538, 756 cm⁻¹

2-[2-(4-Pyridyl)ethylamino]acetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide dihydrochloride (Compound No.13-7)

IR(KBr): 3424, 2902, 1651 cm⁻¹

mp: 133.7-137.0° C.

3-[N′-Methyl-N′-(4-pyridylmethyl)amino]propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide dihydrochloride (Compound No.13-8)

IR(KBr): 3424, 2901, 2846, 1641 cm⁻¹

1,1-Diisopentyl-3-[3-(4-pyridyl)propyl]urea hydrochloride (Compound No.13-9)

IR(KBr): 3082, 2956, 2869, 2614, 1626, 1526 cm⁻¹

mp: 120.5-131.7° C.

1-[3-(1-Adamantyl)propyl]-1-propyl-3-[3-(4-pyridyl)propyl]urea phosphate(Compound No. 13-10)

IR(KBr): 3517, 3423, 1642, 1594, 1539, 1508 cm⁻¹

mp: 148.0-149.0° C.

EXAMPLE 141-[2-(1-Adamantyl)ethyl]-3-[3-hydroxy-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 14-1)

A solution of1-[2-(1-adamantyl)ethyl]-3-[3-(t-butyldimethylsilyloxy)-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 1-138) (136 mg, 0.250 mmol) in 10% hydrogenchloride-methanol (2.3 ml) was stirred at room temperature for threedays. The solvent was evaporated under reduced pressure, the residue wasdistributed with ethyl acetate (50 ml), water (30 ml) and a 1 N aqueoussodium hydroxide solution (20 ml), and the organic layer was washed witha saturated aqueous sodium chloride solution (40 ml). The organic layerwas dried over anhydrous anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the titled compound (59.2 mg,colorless noncrystalline powder, 55.3%).

IR(neat): 3339, 2904, 2847, 1622, 1605, 1532 cm⁻¹

EXAMPLE 15cis-1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[2-(4-pyridyl)cyclopropylmethyl]urea(Compound No. 15-1)

A 1.0 M solution of diethylzinc in hexane (3.1 ml, 3.1 mmol) andchloroiodomethane (0.44 ml, 6.1 mol) were added to a solution of(Z)-1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea(Compound No. 1-111) in anhydrous 1,2-dichloroethane (3 ml) under anitrogen atmosphere and ice-cooling, and the mixture was stirred for onehour. A saturated aqueous ammonium chloride solution (10 ml) was addedto the reaction mixture under ice-cooling, and the whole was stirred atroom temperature for 20 minutes and distributed with ethyl acetate (20ml) and a saturated aqueous ammonium chloride solution (10 ml). Theorganic layer was washed with a saturated aqueous sodium chloridesolution (10 ml) and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography to give 9.0 mg (3.5%) ofthe titled compound as colorless crystals.

IR(KBr): 3340, 3025, 2903, 2847, 1617, 1603, 1525 cm⁻¹

mp: 128.0-130.0° C.

EXAMPLE 16 4-[3-[3-[2-(1-Adamantyl)ethyl]-3-pentylureido]propyl]pyridineN-oxide (Compound No. 16-1)

m-Chloroperbenzoic acid (2.5 g, 15 mmol) was added to a solution of1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (CompoundNo. 1-1) (3.0 g, 7.3 mmol) at room temperature under a nitrogenatmosphere, and the mixture was stirred overnight. The reaction mixturewas distributed with chloroform (20 ml) and a 1 N aqueous sodiumhydroxide solution (60 ml). The organic layer was washed with water (10ml) and a saturated aqueous sodium chloride solution (10 ml)successively and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography to give 2.92 g (94.2%) ofthe titled compound.

IR(KBr): 3346, 2902, 2845, 1622, 1538, 1217, 1178 cm⁻¹

mp: 97.8-127.0° C.

EXAMPLE 171-[2-(1-Adamantyl)ethyl]-1-[2-[N-(2-methoxyethyl)-N-methylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 17-1)

To N,N-dimethylformamide (20 ml) were added1-[2-(1-adamantyl)ethyl]-1-(2-methylaminoethyl)-3-[3-(4-pyridyl)propyl]urea(1.50 g, 3.76 mmol), which was a free base of Compound No. 3-1,potassium carbonate (1.56 g, 11.3 mmol) and sodium iodide (1.69 g, 11.3mmol) at room temperature, then 2-chloroethyl methyl ether (412 μl, 4.51mmol) was added to the mixture, and the whole was heated at 80° C. Thewhole was stirred overnight, diethyl ether (50 ml) and water (100 ml)were added to the reaction mixture, and the whole was extracted. Theobtained organic layer was washed with water (100 ml) and a saturatedaqueous sodium chloride solution (50 ml), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give 552 mg (32.1%) ofthe titled compound as a pale yellow oily matter.

IR(neat): 3350, 2901, 1643, 1602, 1531 cm⁻¹

EXAMPLE 18 2-[2-(4-Pyridyl)ethylamino]acetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 18-1)

Bromoacetic acid (0.50 g, 3.6 mmol) was dissolved in anhydroustetrahydrofuran (20 ml), and the solution was stirred at −15° C. under anitrogen atmosphere. N-Methylmorpholine (0.40 ml, 3.6 mmol) and isobutylchlorocarbonate (0.45 ml, 3.5 mmol) were added to the solution. Then, asolution of a free base of 2-(1-adamantyl)-N-pentylethylaminehydrochloride (Intermediate No. 1-1) (1.0 g, 3.5 mmol) in anhydroustetrahydrofuran (20 ml) was added dropwise to the mixture. The whole wasstirred at 0° C. for 1.5 hours, a saturated aqueous sodiumhydrogencarbonate solution (70 ml) and ethyl acetate (70 ml) were addedto the reaction mixture, and the reaction mixture was distributed. Theethyl acetate layer was washed with water (70 ml) and a saturatedaqueous sodium chloride solution (70 ml) successively and dried overanhydrous magnesium sulfate. The ethyl acetate layer was concentratedunder reduced pressure to give 1.3 g (quantitatively) of 2-bromoaceticacid N-[2-(1-adamantyl)ethyl]-N-pentylamide as a oily matter.

Next, 2-bromoacetic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide (1.3 g,3.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 ml),potassium carbonate (1.5 g, 11 mmol), methyl iodide (1.6 g, 11 mmol) and4-(2-aminoethyl)pyridine (0.43 g, 3.5 mmol) were added to the solution,and the mixture was stirred at an external temperature of 75° C.overnight. Water (100 ml) and diethyl ether (100 ml) were added to thereaction mixture, the reaction mixture was distributed, and the diethylether layer was washed with water (70 ml) twice and a saturated aqueoussodium chloride solution (120 ml) once successively and dried overanhydrous magnesium sulfate. The diethyl ether layer was concentratedunder reduced pressure, and the concentrate was purified by silica gelcolumn chromatography to give 0.6 g (40%) of the titled compound as anoily matter.

IR(neat): 3312, 2902, 2846, 1651, 1602, 1454 cm⁻¹

The following compounds were obtained by a method similar to Example 18.

3-[N′-Methyl-N′-(4-pyridylmethyl)]aminopropionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 18-2)

IR(neat): 2902, 2846, 1643 cm⁻¹

2-[2-(4-Pyridyl)ethoxy]acetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 18-3)

IR(neat): 2902, 2846, 1650, 1602, 1451, 1113 cm⁻¹

EXAMPLE 19 (R)-1-[2-(4-Pyridyl)ethyl]-2-pyrrolidinecarboxylic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide hydrochloride (Compound No. 19-1)

N-t-Butoxycarbonyl-L-proline (1.7 g, 8.0 mmol) was dissolved inanhydrous tetrahydrofuran (20 ml), and the solution was stirred at −15°C. under a nitrogen atmosphere. N-Methylmorpholine (0.90 ml, 8.0 mmol)and isobutyl chlorocarbonate (1.0 ml, 8.0 mmol) were added to thesolution. After 10 minutes, a solution of a free base (2.0 g, 8.0 mmol)of Intermediate No. 1-1 in anhydrous tetrahydrofuran (20 ml) was addeddropwise to the mixture over five minutes. The whole was stirred at 0°C. for 45 minutes, then the temperature was raised to room temperature,and the whole was stirred overnight. A saturated aqueous sodiumhydrogencarbonate solution (50 ml) and ethyl acetate (50 ml) were addedto the reaction mixture, and the reaction mixture was distributed. Theethyl acetate layer was washed with a 10% aqueous citric acid solution(50 ml), water (50 ml) and a saturated aqueous sodium chloride solution(50 ml) successively and dried over anhydrous magnesium sulfate. Theethyl acetate layer was concentrated under reduced pressure, and theconcentrate was purified by silica gel column chromatography to give 1.9g (52%) of (R)-1-(t-butoxycarbonyl)-2-pyrrolidinecarboxylic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide, which was the target compound,as an oily matter.

Next, 4 N hydrogen chloride/dioxane (20 ml, 81 mmol) was added to(R)-1-(t-butoxycarbonyl)-2-pyrrolidinecarboxylic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (1.8 g, 4.0 mmol) underice-cooling, then the temperature was raised to room temperature, andthe mixture was stirred for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure to give 1.5 g (quantitatively) of(R)-2-pyrrolidinecarboxylic acid N-[2-(1-adamantyl)ethyl]-N-pentylamidehydrochloride as a noncrystalline solid.

Next, (R)-2-pyrrolidinecarboxylic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide hydrochloride (1.4 g, 3.7 mmol)was dissolved in anhydrous N,N-dimethylformamide (40 ml), potassiumcarbonate (2.6 g, 19 mmol), methyl iodide (1.7 g, 11 mmol) and4-(2-chloroethyl)pyridine hydrochloride (0.70 g, 3.7 mmol) were added tothe solution, and the mixture was stirred at an external temperature of80° C. overnight. A 2 N aqueous sodium hydroxide solution (70 ml) anddiethyl ether (70 ml) were added to the reaction mixture, the reactionmixture was distributed, and the diethyl ether layer was washed withwater (70 ml) and a saturated aqueous sodium chloride solution (70 ml)successively and dried over anhydrous magnesium sulfate. The diethylether layer was concentrated under reduced pressure, and the concentratewas purified by silica gel column chromatography to give 0.80 g (47%) ofthe titled compound as an oily matter.

IR(neat): 2902, 2846, 1644 cm⁻¹

[α]²⁰ _(D): −48.1° (MeOH, C 1.0)

The following compound was obtained by a method similar to Example 19.

(S)-1-[2-(4-Pyridyl)ethyl]-2-pyrrolidinecarboxylic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide hydrochloride (Compound No. 19-2)

IR(neat): 2902, 2846, 1644, 1601 cm⁻¹

[α]²⁰ _(D): +41.6° (MeOH, C 1.0)

EXAMPLE 201-[2-(1-Adamantyl)ethyl]-1-[2-(N-ethylamino)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 20-1)

Lithium aluminum hydride (890 mg, 23.5 mmol) was suspended in anhydrousdiethyl ether (10 ml) under a nitrogen atmosphere, and a solution of1-[2-(acetylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-103) (4.86 g, 11.4 mmol) in anhydrous tetrahydrofuran(60 ml) was added dropwise to the suspension under ice-cooling withstirring over two hours. The temperature was raised to room temperature,and the mixture was stirred for 70 hours. Ethyl acetate (25 ml) wasadded to the reaction mixture under ice-cooling, then a 1 N aqueoussodium hydroxide solution (25 ml) was added thereto, and the whole wasfiltered with Celite to remove an insoluble matter. The filtrate wasdistributed with ethyl acetate (25 ml) and water (25 ml), and theorganic layer was washed with a saturated aqueous sodium chloridesolution (20 ml). The organic layer was dried over anhydrous magnesiumsulfate, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitled compound (2.33 g, colorless crystals, 49.8%).

IR(KBr): 3309, 2901, 2845, 1615, 1534 cm⁻¹

mp: 96.8-104.9° C.

EXAMPLE 21 3-(4-Pyridylmethylideneamino)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 21-1)

3-(t-Butoxycarbonylamino)propionic acid (1.0 g, 5.3 mmol) was dissolvedin anhydrous tetrahydrofuran (15 ml), and N-methylmorpholine (0.6 ml,5.5 mmol) was added to the solution. The mixture was stirred at −15° C.,and isobutyl chlorocarbonate (0.7 ml, 5.4 mmol) was added thereto. Then,a solution of a free base of 2-(1-adamantyl)-N-pentylethylaminehydrochloride (Intermediate No. 1-1) (1.5 g, 5.3 mmol) in anhydroustetrahydrofuran (15 ml) was added thereto at −18° C. The whole wasstirred at 0° C. for 1.5 hours, ethyl acetate (100 ml) and a saturatedaqueous sodium hydrogencarbonate solution (100 ml) were added to thereaction mixture, and the reaction mixture was distributed. The organiclayer was washed with a 10% aqueous citric acid solution (100 ml), water(100 ml) and a saturated aqueous sodium chloride solution (100 ml)successively and dried over anhydrous magnesium sulfate. The organiclayer was concentrated under reduced pressure, and the concentrate waspurified by silica gel column chromatography to give 1.9 g (85%) of3-(t-butoxycarbonylamino)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide as an oily matter.

A 4.0 N hydrogen chloride/1,4-dioxane solution (22 ml, 88 mmol) wasadded to 3-(t-butoxycarbonylamino)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (1.9 g, 4.4 mmol) underice-cooling, then the temperature was raised to room temperature, andthe mixture was stirred for one hour 15 minutes. The reaction mixturewas concentrated under reduced pressure to give 1.4 g (89%) of thetarget hydrochloride. A 1 N aqueous sodium hydroxide solution (80 ml)was added to the hydrochloride, and the whole was extracted withchloroform (80 ml). The chloroform layer was washed with a saturatedaqueous sodium chloride solution (80 ml) and dried over anhydrousmagnesium sulfate. The chloroform layer was concentrated under reducedpressure to give 3-aminopropionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide as an oily matter.

3-Aminopropionic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide (1.3 g, 3.9mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and thesolution was stirred under ice-cooling. 4-Pyridinecarboxyaldehyde (0.42ml, 4.3 mmol) was added to the solution, and the mixture was stirred atroom temperature for three hours. The reaction mixture was concentratedunder reduced pressure to give 1.7 g (quantitatively) of the titledcompound as an oily matter.

IR(neat): 2901, 1713, 1644, 1454 cm⁻¹

EXAMPLE 22 3-(4-Pyridylmethylamino)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 22-1)

3-(4-Pyridylmethylideneamino)propionic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 21-1) (1.6 g, 3.9mmol) was dissolved in methanol, 10% palladium on carbon (catalyticamount) was added to the solution, and the mixture was stirred underhydrogen at 1 atm and room temperature for seven hours. The 10%palladium on carbon was filtered out, the filtrate was concentratedunder reduced pressure, and the concentrate was purified by silica gelcolumn chromatography to give 0.58 g (36%) of the titled compound as anoily matter.

IR(neat): 3313, 2902, 2846, 1636, 1451 cm⁻¹

EXAMPLE 231-[2-(1-Adamantyl)ethyl]-3-[3-[4-(2-cyano)pyridyl]propyl]-1-pentylurea(Compound No. 23-1)

Trimethylsilyl cyanide (1.2 ml, 9.4 mmol) and triethylamine (0.65 ml,4.7 mmol) were added to a solution of4-[3-[3-[2-(1-adamantyl)ethyl]-3-pentylureido]propyl]pyridine N-oxide(Compound No. 16-1) (1.0 g, 2.3 mmol) in anhydrous acetonitrile (1.5 ml)at room temperature under a nitrogen atmosphere, and the mixture wasrefluxed overnight. The reaction mixture was distributed with chloroform(40 ml) and a saturated aqueous sodium hydrogencarbonate solution (40ml). The organic layer was washed with a saturated aqueous sodiumchloride solution (10 ml) and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the resultingresidue was filtered off with diisopropyl ether to give 730 mg (73.0%)of the titled compound as crystals.

IR(KBr): 3334, 2900, 2845, 2234, 1621, 1534 cm⁻¹

mp: 112.0-123.0° C.

EXAMPLE 241-[2-(1-Adamantyl)ethyl]-3-[3-[4-(2-aminomethyl)pyridyl]propyl]-1-pentylurea(Compound No. 24-1)

A catalytic amount of 10% palladium on carbon was added to a solution of1-[2-(1-adamantyl)ethyl]-3-[3-[4-(2-cyano)pyridyl]propyl]-1-pentylurea(Compound No. 23-1) (0.20 g, 0.46 mmol) in methanol (2.0 ml) at roomtemperature under a nitrogen atmosphere, and the mixture was stirredunder a hydrogen atmosphere overnight. The reaction mixture was filteredwith Celite, the solvent was evaporated under reduced pressure, and theresulting residue was distributed with diethyl ether (50 ml) and water(50 ml). A 2 N aqueous sodium hydroxide solution (10 ml) was added tothe aqueous layer, and the whole was further extracted with diethylether (50 ml). The combined organic layer was washed with a saturatedaqueous sodium chloride solution (10 ml) and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the resulting residue was filtered off with diisopropyl ether togive 151 mg (74.4%) of the titled compound as crystals.

IR(KBr): 3346, 2901, 2845; 1621, 1538 cm⁻¹

mp: 88.0-95.0° C.

EXAMPLE 251-[2-(1-Adamantyl)ethyl]-3-[3-[4-(2-carboxy)pyridyl]propyl]-1-pentylurea(Compound No. 25-1)

At room temperature, 6 N hydrochloric acid (1.5 ml, 9.2 mmol) was addedto1-[2-(1-adamantyl)ethyl]-3-[3-[4-(2-cyano)pyridyl]propyl]-1-pentylurea(Compound No. 23-1) (0.20 g, 0.46 mmol), and the mixture was refluxedovernight. The solvent was evaporated under reduced pressure from thereaction mixture, and the resulting crystals were filtered off withacetone. The crystals were dissolved in chloroform (40 ml), and thesolution was washed with water (40 ml) and a saturated aqueous sodiumchloride solution (10 ml) successively. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give 132 mg (63.0%) of the titled compound.

IR(KBr): 3326, 2905, 2848, 1704, 1621, 1539 cm⁻¹

mp: 130° C.

EXAMPLE 261-[2-(1-Adamantyl)ethyl]-3-[3-[4-(2-hydroxymethyl)pyridyl]propyl]-1-pentylurea(Compound No. 26-1)

A 1.0 M solution of a borane-tetrahydrofuran complex in tetrahydrofuran(0.66 ml, 0.66 mmol) was added to a solution of1-[2-(1-adamantyl)ethyl]-3-[3-[4-(2-carboxy)pyridyl]propyl]-1-pentylurea(Compound No. 25-1) (0.10 g, 0.22 mmol) in anhydrous tetrahydrofuran(0.7 ml) under a nitrogen atmosphere and ice-cooling, and the mixturewas stirred at room temperature for 4.5 hours. Water (3 ml) was added tothe reaction mixture under ice-cooling, and the reaction mixture wasdistributed with ethyl acetate (15 ml) and a 0.1% aqueous sodiumhydroxide solution (10 ml). The organic layer was washed with asaturated aqueous sodium chloride solution (10 ml) and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography to give 53 mg of a borane complex salt of the titledcompound as an oily matter.

IR(neat): 3342, 2904, 1630, 1531 cm⁻¹

EXAMPLE 271-[2-(1-Adamantyl)ethyl]-3-[3-[4-(2-methyl)pyridyl]propyl]-1-pentylurea(Compound No. 27-1)

p-Toluenesulfonyl chloride (23 mg, 0.12 mmol) was added to a solution of1-[2-(1-Adamantyl)ethyl]-3-[3-[4-(2-hydroxymethyl)pyridyl]propyl]-1-pentylurea(Compound No. 26-1) (50 mg, 0.11 mmol) and triethylamine (20 μl, 0.13mmol) in anhydrous dichloromethane (1.0 ml) at room temperature, and themixture was stirred at room temperature overnight. The reaction mixturewas distributed with chloroform (9 ml) and water (10 ml), and theorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the resulting residue waspurified by silica gel column chromotography. A catalytic amount of 10%palladium on carbon was added to a solution of the obtainedp-toluenesulfonyl form in methanol (1 ml), and the mixture was stirredunder a hydrogen atmosphere for seven days to give 18 mg (38%) of thetitled compound as an oily matter.

IR(neat): 3345, 2903, 2847, 1624, 1534 cm⁻¹

EXAMPLE 281-[2-(1-Adamantyl)ethyl]-1-(2-aminoethyl)-3-[3-(4-pyridyl)propyl]urea(Compound No. 28-1)

Under ice-cooling, 6 N hydrochloric acid (15 ml) was added to a solutionof1-[2-(acetylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea(Compound No. 1-103) (1.02 g, 2.39 mmol) in methanol (10 ml), and themixture was heated at 90° C. with stirring for three days. The reactionmixture was neutralized with a 1 N aqueous sodium hydroxide solution (10ml), chloroform (50 ml) and water (10 ml) were added thereto, and layerswere separated. The organic layer was washed with a saturated aqueoussodium chloride solution (50 ml) and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to give 200 mg(21.7%) of the titled compound as an oily matter.

IR(neat): 3306, 2902, 2846, 1629, 1605, 1537, 753 cm⁻¹

EXAMPLE 294-[2-[N-[2-(1-Adamantyl)ethyl]-N-pentylcarbonylmethoxy]ethoxy]-pyridineN-oxide (Compound No. 29-1)

2-(1-Adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1)(0.50 g, 1.7 mmol) was added to a solution of diglycolyl chloride (0.31ml, 2.6 mmol) and triethylamine (0.70 ml, 5.1 mmol) in anhydrousdichloromethane (6 ml) under ice-cooling, and the mixture was stirred atroom temperature overnight. Methanol (5 ml) was added to the reactionmixture, and the whole was stirred for three hours. The solvent wasevaporated under reduced pressure, the residue was distributed withethyl acetate and water (15 ml respectively), and the organic layer waswashed with a saturated aqueous sodium chloride solution (5 ml) anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography to give 0.39 g (60%) of2-methoxycarbonylmethoxyacetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide as an oily matter.

Next, sodium borohydride (0.18 g, 4.8 mmol) was added to a solution of2-methoxycarbonylmethoxyacetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (0.37 g, 0.96 mmol) in methanol(3 ml) under ice-cooling, and the mixture was stirred at roomtemperature overnight. Water (10 ml) was added to the reaction mixture,and the whole was stirred for 10 minutes. Then, water (20 ml) and ethylacetate (30 ml) were added thereto, and layers were separated. Theorganic layer was washed with a saturated aqueous sodium chloridesolution (10 ml) and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography to give 74 mg (22%) of2-(2-hydroxyethoxy)acetic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide asan oily matter.

Next, 4-nitropyridine N-oxide (24 mg, 0.17 mmol) and potassium carbonate(28 mg, 0.20 mmol) were added to a solution of 2-(2-hydroxyethoxy)aceticacid N-[2-(1-adamantyl)ethyl]-N-pentylamide (60 mg, 0.17 mmol) inN,N-dimethylformamide (0.4 ml) at room temperature, and the mixture wasstirred at 60° C. for two days. The solvent was evaporated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography to give 39 mg of the titled compound as an oily matter.

¹H-NMR (400 MHz, CDCl₃) δ0.87-0.93 (m, 3H), 1.20-1.40 (m, 6H), 1.47-1.60(m, 8H), 1.61-1.67 (m, 3H), 1.68-1.76 (m, 3H), 1.97 (brs, 3H), 3.10-3.19(m, 2H), 3.25-3.36 (m, 2H), 3.94-3.98 (m, 2H), 4.20-4.27 (m, 4H),6.81-6.86 (m, 2H), 8.10-8.15 (m, 2H)

EXAMPLE 30 2-[2-(4-Pyridyloxy)ethoxy]acetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 30-1)

A catalytic amount of 10% palladium on carbon was added to a solution of4-[2-[N-[2-(1-adamantyl)ethyl]-N-pentylcarbonylmethoxy]ethoxy]-pyridineN-oxide (Compound No. 29-1) (39 mg, 0.088 mmol) and acetic anhydride (20μl, 0.18 mmol) in a mixed solvent of methanol (0.4 ml) and acetic acid(0.1 ml) at room temperature under a nitrogen atmosphere, and themixture was stirred under a hydrogen atmosphere for four days. Thereaction mixture was filtered with Celite, the solvent was evaporatedunder reduced pressure from the filtrate, and the residue wasdistributed with ethyl acetate (20 ml) and a saturated aqueous sodiumhydrogencarbonate solution (20 ml). The organic layer was washed with asaturated aqueous sodium chloride solution (10 ml) and dried overanhydrous magnesium sulfate. The solvent was evaporated, and theresulting residue was purified by silica gel column chromatography togive 16 mg (42%) of the titled compound as an oily matter.

IR(neat): 2903, 1651, 1592 cm⁻¹

EXAMPLE 311-[2-(1-Adamantyl)ethyl]-3-[3-oxo-3-(4-pyridyl)propyl]-1-pentylurea(Compound No. 31-1)

1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (221 mg, 0.520mmol) was added to a solution of1-[2-(1-adamantyl)ethyl]-3-[3-hydroxy-3-(4-pyridyl)propyl]-1-pentylurea(100 mg, 0.234 mmol) in anhydrous dichloromethane (2 ml) underice-cooling, the temperature was raised to room temperature, and themixture was stirred for one hour. The reaction mixture was cooled withice again, ethyl acetate (10 ml), a saturated aqueous sodium sulfitesolution (5 ml) and a saturated aqueous sodium hydrogencarbonatesolution (5 ml) were added to the reaction mixture, and the whole wasstirred for 15 minutes. The reaction mixture was distributed with ethylacetate (50 ml) and water (10 ml), and the organic layer was washed witha saturated aqueous sodium sulfite solution (5 ml), a saturated aqueoussodium hydrogencarbonate solution (5 ml) and a saturated aqueous sodiumchloride solution (25 ml) successively. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give 87.3 mg (87.8%) of the titled compound ascolorless crystals.

IR(KBr): 3328, 2901, 2847, 1710, 1619, 1540 cm⁻¹

mp: 103.5-104.0° C.

[C] Formulation

General formulation examples of oral preparations and injections usingthe present compounds are shown below.

1) Tablet Formulation 1 (in 100 mg) Present compound 1 mg Lactose 66.4mg   Cornstarch 20 mg  Calcium carboxymethylcellulose 6 mgHydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg  

Tablets according to the formulation as above are coated with 2mg/tablet of a coating agent (this is a conventional coating agent suchas hydroxypropylmethylcellulose, macrogol or silicone resin) to obtaindesired coated tablets. (The same is applied to tablets mentionedbelow.) Desired tablets can be obtained by changing the amounts of thepresent compound and the additives appropriately.

2) Capsule Formulation 1 (in 150 mg) Present compound  5 mg Lactose 145mg

Desired capsules can be obtained by changing the mixing ratio of thepresent compound to lactose appropriately.

3) Injection Formulation 1 (in 10 ml) Present compound 10-100 mg Sodiumchloride   90 mg Sodium hydroxide q.s. Hydrochloric acid q.s. Sterilepurified water q.s.

Desired injections can be obtained by changing the mixing ratio of thepresent compound to the additives appropriately.

[D] Pharmacological Test

Inhibitory effects on TNF-α production induced by lipopolysaccharide(LPS) stimulation were studied by in vivo tests according to the methodof Tsuji et al. (Inflamm. res. 46 (1997) 193-198).

Female rats (five per group), body weight of about 200 g, about eightweeks old, were used as test animals. LPS from Salmonella was dissolvedin physiological saline to prepare an LPS solution (1 mg/ml). Each testsubstance was dissolved or uniformly suspended in a 1% methylcellulosesolution to give test substance-preparation liquids.

The above-mentioned LPS solution (0.5 ml/kg) was administered to afootpad of the rat. Immediately after the LPS administration, the testsubstance preparation liquid (containing 10 mg/kg or 3 mg/kg testsubstance) was orally administered. Two hours after the LPSadministration, blood was collected from abdominal aorta and wascentrifuged at 4° C. and 3000 rpm for ten minutes. TNF-α levels in theobtained plasma were measured with a rat TNF-α-specific ELISA kit. TNF-αwas not observed in the plasma with respect to an LPS-non-administeredgroup (control).

Inhibition rates of TNF-α production of the test substances weredetermined by the following equation.

Inhibition rate (%)=[(A−B)/A]×100

-   A: TNF-α level in plasma of test substance-nonadministered group-   B: TNF-α level in plasma of test substance-administered group

(Results)

Calculating TNF-α production inhibition rates (%) when administered thetest substances (10 mg/kg or 3 mg/kg) orally to the rats, many of thepresent compounds exhibited high inhibition rates of production. Table 1shows typical test results by oral administration of 10 mg/kg, and Table2 shows typical test results by oral administration of 3 mg/kg.

TABLE 1 Test substance Inhibition rate (%) Compound No. 1-1 92.1Compound No. 1-18 78.9 Compound No. 1-20 60.0 Compound No. 1-22 87.0Compound No. 1-24 95.8 Compound No. 1-25 89.0 Compound No. 1-26 95.5Compound No. 1-27 81.3 Compound No. 1-28 90.4 Compound No. 1-31 92.6Compound No. 1-32 62.4 Compound No. 1-34 70.8 Compound No. 1-35 82.5Compound No. 1-37 84.3 Compound No. 1-38 92.3 Compound No. 1-42 86.7Compound No. 1-43 67.6 Compound No. 1-44 93.7 Compound No. 1-45 91.1Compound No. 1-55 78.1 Compound No. 1-66 79.4 Compound No. 1-68 79.0Compound No. 1-70 87.9 Compound No. 1-120 95.1 Compound No. 1-139 94.1Compound No. 2-1 91.5 Compound No. 2-3 51.8 Compound No. 6-1 50.5Compound No. 7-1 71.5 Compound No. 11-1 50.8

TABLE 2 Test substance Inhibition rate (%) Compound No. 1-10 63.0Compound No. 1-78 61.5 Compound No. 1-84 35.5 Compound No. 1-95 70.8Compound No. 1-111 85.1 Compound No. 1-137 82.1 Compound No. 2-7 78.7Compound No. 2-9 84.5 Compound No. 2-11 53.5 Compound No. 2-14 87.3Compound No. 2-15 68.1 Compound No. 2-18 87.3 Compound No. 2-20 82.1Compound No. 3-4 76.1 Compound No. 4-1 42.8 Compound No. 5-3 49.4Compound No. 5-4 62.6 Compound No. 5-5 42.8 Compound No. 5-6 41.7Compound No. 10-16 62.8 Compound No. 10-17 53.8 Compound No. 14-1 36.3Compound No. 15-1 73.8 Compound No. 16-1 74.3 Compound No. 18-1 55.7Compound No. 18-3 56.6 Compound No. 27-1 68.6 Compound No. 31-1 46.8

INDUSTRIAL APPLICABILITY

The results of the pharmacological test clearly show that since thepresent compounds have excellent TNF-α production inhibitory effects,the present compounds can be applied to extensive medical uses astherapeutic agents for diseases in which TNF-α participates, forexample, autoimmune diseases such as rheumatoid arthritis, Crohn'sdisease and systemic lupus erythematosus, cachexia, acute infectiousdisease, allergy, pyrexia, anemia, diabetes and the like.

1. A compound represented by the following formula [1] or a saltthereof,

wherein A is —(CR⁵R⁶)— or —O—; B is alkylene or alkenylene optionallycontaining —O—, —S—, —(NR⁷)— or —CO—, R¹ and R² being the same ordifferent, are alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl,wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl isoptionally substituted by halogen, cycloalkyl, aryl or adamantyl; R³ isa substituted or unsubstituted pyridine ring; R⁵ and R⁶ being the sameor different, are hydrogen or alkyl; R⁷ is hydrogen or alkyl; and X is Oor S.
 2. The compound or a salt thereof as claimed in claim 1, whereinat least one of R¹ and R² is adamantylalkyl.
 3. The compound or a saltthereof as claimed in claim 1, wherein A is —(CR⁵R⁶)— or —O—; B isalkylene or alkenylene optionally containing —O—, —S—, —(NR⁷)—, —CO—, or—N═; R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, whereinthe alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionallysubstituted by halogen, cycloalkyl, aryl, or adamantyl; R² isadamantylalkyl; R³ is a substituted or unsubstituted pyridine ring; R⁵and R⁶, being the same or different, are hydrogen, or alkyl; R⁷ ishydrogen or alkyl; and X is O or S.
 4. The compound or a salt thereof asclaimed in claim 3, wherein R² is adamantylalkyl and R³ is a pyridinering.
 5. The compound or a salt thereof as claimed in claim 3, wherein Ais —(CR⁵R⁶)— or —O—; B is alkylene or alkenylene which optionallycontains —S—; R¹ is alkyl or alkenyl, wherein the alkyl is optionallysubstituted by halogen; R² is adamantylalkyl; R³ is a pyridine ring; R⁵and R⁶ are hydrogen; and X is O.
 6. A compound selected from the groupconsisting of 5-(4-pyridyl)valeric acidN-[2-(1-adamantyl)ethyl]-N-pentylamide, 3-(4-pyridylmethylthio)propionicacid N-[2-(1-adamantyl)ethyl]-N-pentylamide,2-[2-(4-pyridyl)ethylthio]acetic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide, and 6-(4-pyridyl)caproic acidN-[2-(1-adamantyl)ethyl]-N-pentylamide or a salt thereof.
 7. Thecompound or a salt thereof as claimed in claim 1, wherein A is —(CR⁵R⁶)—or —O—; B is alkylene or alkenylene optionally containing —O—, —S—,—(NR⁷)— or —N═; R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, orcycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl is optionally substituted by halogen, cycloalkyl, or aryl;R² is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or arylalkyl; R³ is apyridine ring; R⁵ and R⁶, being the same or different, are hydrogen oralkyl; R⁷ is hydrogen or alkyl; and X is O or S.
 8. The compound or asalt thereof as claimed in claim 7, wherein A is —(CR⁵R⁶)—; B isalkylene or alkenylene; R¹ is alkyl or alkenyl; R² is arylalkyl; R³ is apyridine ring; R⁵ and R⁶ are hydrogen; and X is O.
 9. The compound or asalt thereof as claimed in claim 8, wherein R¹ is alkyl and R² isarylalkyl.
 10. 5-(4-pyridyl)valeric acid N-pentyl-N-phenethylamide or asalt thereof.
 11. The compound or a salt thereof as claimed in claim 7,wherein A is —(CR⁵R⁶)—; B is alkylene or alkenylene; R¹ is alkyl,alkenyl or cycloalkyl, wherein the alkyl is optionally substituted byhalogen, cycloalkyl, or aryl; R² is cycloalkylalkyl; R³ is a pyridinering; R⁵ and R⁶ are hydrogen; and X is O.
 12. A pharmaceuticalcomposition comprising the compound or a salt thereof as claimed inclaim 1 as an active ingredient and a pharmacologically acceptableadditive.